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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 13  |  Issue : 3  |  Page : 178-196

Biochemical features of blood vessel extracellular calcium-sensing receptor and their physiological mechanism of action in the regulation of vascular tone and blood pressure


Department of Biomedical Sciences, College of Health Sciences, Arsi University, Assela, Oromia, Ethiopia

Date of Submission21-Mar-2020
Date of Acceptance22-Apr-2020
Date of Web Publication05-Oct-2020

Correspondence Address:
Mr. Leta Melaku
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Assela, Oromia
Ethiopia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_94_20

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  Abstract 

The extracellular calcium-sensing receptor (CaR) is a G protein coupled receptor superfamily that has ability to sense very small changes in extracellular Ca2+ with primary physiological function of maintenance of constant blood Ca2+ levels. In addition to being expressed in tissues involved in [Ca2+]o homeostasis, it is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions such as control vasomotor tone and blood pressure. However, the exact cellular mechanisms involved in these responses remain unclear. Stimulation of CaRs on perivascular nerves is proposed to evoke synthesis and release of nitric oxide (NO) from pre-synaptic terminals, which activate large conductance Ca2+-activated K+ channels in adjacent VSMCs that induce membrane hyperpolarisation and subsequent vasorelaxation. Plus, activation of CaRs on endothelial cells is reported to generate NO or vasoactive lipids or induce activation of intermediate conductance Ca2+-activated K+ channels to induce vasorelaxations. In contrast, CaR-induced activation of Gq and MAPK kinase-mediated pathways in VSMCs are linked to vasoconstriction and cell proliferation respectively. Taken together, these findings indicate that stimulation of vascular CaRs is reported to induce both constrictions and relaxations. In the endothelium intact artery, CaR mediated vasorelaxations are the dominant physiological phenomenon.

Keywords: Calcium, calcium-sensing receptors, vascular tone and blood pressure


How to cite this article:
Melaku L, Amsalu L. Biochemical features of blood vessel extracellular calcium-sensing receptor and their physiological mechanism of action in the regulation of vascular tone and blood pressure. Indian J Health Sci Biomed Res 2020;13:178-96

How to cite this URL:
Melaku L, Amsalu L. Biochemical features of blood vessel extracellular calcium-sensing receptor and their physiological mechanism of action in the regulation of vascular tone and blood pressure. Indian J Health Sci Biomed Res [serial online] 2020 [cited 2020 Oct 28];13:178-96. Available from: https://www.ijournalhs.org/text.asp?2020/13/3/178/297198


  Introduction Top


Humphry Davy first recognized calcium as an element in 1808 and the name was given after the Latin for lime: calx.[1] Calcium is the fifth most abundant element, 1000 – 1200g, in adult human.[2] Approximately 99% of body calcium resides in the bones and teeth as the hydroxyapatite [Ca10(PO4)6(OH)2] crystal.[3],[4] From remaining 1%, about 0.9% is found intracellularly within the soft tissues and less than 0.1% is present in the ECF.[5] The normal serum calcium level is ~8.8 to 10.4 mg/dl (2.2 to 2.6 mmol/L)[6] and it is present in three forms: about 50% is free ionized,[7] about 10% is combined with various anions (bicarbonate, citrate, phosphate, lactate, and sulphate)[8] and the remaining 40% is bound to serum proteins, mainly serum albumin.[9] The importance of calcium ions in the regulation of physiological functions has been known since the 19th century.[10] The free ionized calcium is responsible for a variety of physiological processes including neuromuscular transmission, muscle contraction, cardiac automaticity, nerve function, hormone secretion, cell division and movement, intercellular adhesion, and cell motility and certain oxidative processes.[11],[12],[13],[14] It is also a co-factor for many steps during blood coagulation.[15] Calcium is also a major intracellular messenger in many intracellular responses to chemical and electrical stimuli and required by many enzymes for full activity.[16],[17] The extracellular fluid (ECF) ionized calcium (1.0 – 1.25 mmol/L) concentration is 10,000 times higher than the concentration of the intracellular fluid (ICF) ionized calcium.[18] Intracellular fluid ionized calcium is at low level because cell membrane permeability to Ca 2+ is low and cells also have powerful mechanisms for extrusion, sequestration and buffering of calcium.[16] Nevertheless, total calcium concentration in the cell interior varies during normal function by up to 10-fold (e. g. from 10-4 to 10-3 mmol/L).[19] The plasma ionized calcium concentration is tightly maintained mainly by action of three main calciotropic hormones (parathyroid hormone, calcitriol and calcitonin) [Figure 1] and other nutrients, most notably magnesium and phosphorus.[20],[21],[22]
Figure 1: Systematic regulation of Ca2+ homeostasis in human body. If the Ca2+ level is too low, parathyroid hormone is released from parathyroid glands. It then stimulates Ca2+ uptake from intestines, increases the rate of Ca2+ release from bone and the rate of Ca2+ reabsorption in the urinary system. If the Ca2+ level is too high, the opposite regulation will occur to control the blood Ca2+ level. Thus, the blood Ca2+ is strictly maintained between 1.1 and 1.2 mmol/L

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The way body maintains and regulates extracellular calcium levels is a complex puzzle that has intrigued researchers for decades.[13],[15],[23] One large piece of this puzzle that is falling into place concerns a cell-surface receptor that responds to, or “senses,” extracellular calcium-ion concentrations in parathyroid, kidney and other tissues. Experiments using a RIA to detect PTH levels in whole animals revealed that an increase in the level of free ionized calcium in the serum resulted in a decrease in PTH and that a decrease in serum Ca 2+ caused an increase in PTH levels.[24],[25] Further studies revealed that increase in extracellular Ca 2+ increased the production of both inositol 1, 4, 5 triphosphate and diacylglycerol, which are recognized as components associated with receptor-mediated intracellular Ca 2+ mobilization.[26],[27],[28]

Finally, Nemeth and Scarpa, using the fluorescent indicator fura-2, eloquently demonstrated that extracellular divalent cations evoked rapid and transient increases in intracellular calcium mobilization in bovine parathyroid cells in the absence of Ca 2+ transmembrane influx.[29] This observation, in conjunction with the others mentioned above, provided compelling evidence that there was a receptor at the cell surface of parathyroid cells sensitive to extracellular Ca 2+ that regulated PTH secretion through the mobilization of intracellular Ca 2+. In 1993, a receptor exhibiting molecular sensor of free ionized serum calcium, calcium-sensing receptor (CaSR/CaR) was first cloned from bovine parathyroid gland [30] and then from human parathyroid cells [31] as well as from rat kidney cells.[32] Detection of the CaR by Western blotting revealed that the receptor produced three different protein bands between 100 and 200 kDa that represent different monomeric forms of the CaR.[33],[34] The lowest band, at approximately 120 kDa, is a non-glycosylated form of the CaR that is expressed at a much lower level than the other two forms and is not always detected in Western blots. Two additional bands equivalent to molecular masses of approximately 130 – 140 and approximately 150 – 160 kDa correspond respectively to the immature form of CaR, which is glycosylated with carbohydrates containing high mannose content, and the mature form of the receptor, which is glycosylated with complex carbohydrates. Only the mature form of the receptor is expressed at the cell surface.[34],[35],[36] It has been demonstrated that the CaR is normally expressed at the cell surface as a homodimer, although there have been instances where the CaR has been detected in heterodimeric complexes with another receptor, such as the metabotropic glutamate receptor (mGluR).[34],[37],[38] Although the central role of the CaR is regulation of calcium homeostasis, it is also expressed in non-calciotropic tissues as well to regulate a multitude of cellular processes unrelated to mineral ion homeostasis.[39],[40],[41],[42]


  The Structural Biology of Calcium-Sensing Receptor Top


The gene encoding humans CaR is located on the 3q13.3 – 21 that consists of seven exons [Figure 2].[43],[44] It is under the control of two promoters (the upstream P1 containing a TATA box and a CAAT box, and the downstream P2, which is GC rich) that result in alternative transcripts of exon 1 (exon 1A and exon 1B). It appears that exon 1A has more impact on CaR expression than exon 1B.[45],[46],[47]
Figure 2: Schematic of (A) the calcium-sensing receptor gene promoters, (B) the calcium-sensing receptor gene exon/intron organization, and (C) calcium-sensing receptor protein. (A) CCAAT and TATA boxes and SP-1 are the sites that drive transcription of exon 1A and 1B respectively. Bolded: those shown to be functionally active. Not bolded: those predicted but either not functionally active or not yet evaluated. (B) Exon/intron organization of the calcium-sensing receptor gene. White bars: mRNA untranslated (exons; 1A, 1B, part of 2, part of 7). Gray bars: mRNA protein coding (exons; part of 2, 3–6, part of exon 7). ATG: Initiation codon. TAA: Stop codon. AATAAA: Polyadenylation signals. Alternative splicing of exons 1A and 1B to exon 2 is shown. *Alternative transcript lacking exon 5. Black arrowhead: alternative transcript having additional 30 bases at the beginning of exon 6. (C) Calcium-sensing receptor protein: 1078 amino acid protein encoded by exons 2–7. *Minus 77 aa encoded by exon 5. Open arrowhead: additional 10 aa encoded by extra 30 bases of alternative RNA transcript

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The presence of the two promoter regions suggests tissue-specific CaR promoter regulation and alternatively spliced mRNA transcripts.[48] Exons 2 to 7 encode CaR amino acid.[49]

The human CaR consists of 1078 amino acid residues and belong to glutamate family C of the G protein-coupled receptors (GPCR) or 7 transmembrane receptors.[17],[42],[50] Family C also includes the metabotropic glutamate receptors, GABAB receptors, receptors for taste and pheromones, and an amino acid-and divalent cation-sensing receptor called GPRC6A.[51],[52]

Like all GPCR's, CaR is comprised of the three main structural domains: extracellular domain (ECD); seven transmembrane domain (7TMD); and intracellular carboxyl-terminal domain (ICD) [Figure 3][30],[53],[54] the G proteins, CaR also activates phosphatidylinositol
Figure 3: Structural domains and mutations in the human calcium-sensing receptor. Activating (orange) and inactivating (blue) mutations demonstrate the pivotal role of the calcium-sensing receptor. Several polymorphisms have also been detected (yellow)

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The extracellular domain

Like other subfamilies of glutamate family C, CaR contains a very large extracellular domain, which covers 612 amino acids that includes two clusters of acidic amino acid residues that probably interact with Ca 2+ through electrostatic interactions.[55],[56],[57] From total 612 amino acids of ECD, amino acid residue 36-513 forms two adjacent monomeric lobes, lobe 1 and lobe 2, that are connected by two disulfide bonds involving cysteines 129 and 131 [Figure 4][22],[31],[58] and it's molecular modelling exhibits a bilobed, venus flytrap (VFT)-like structure [Figure 5].[55],[59],[60]
Figure 4: Model of the calcium-sensing receptor based on the known structure of the extracellular domain of mGluR1

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Figure 5: Schematic structure of class C of the G protein-coupled receptors

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The ECD of CaR contains 11 potential N linked glycosylation sites on venus flytrap domain and a total of 19 cysteines, nine of them being highly conserved and located at the end of the ECD and constituting the so-called cysteine-rich domain [Figure 3] and [Figure 6].[61],[62],[63],[64] The eight conserved N linked glycosylation sites, Asn90, Asn130, Asn261, Asn287, Asn446, Asn468, Asn488, and Asn541, was demonstrated to be important for cell surface expression whereas the conserved cysteine rich domain is important for receptor dimerization, cell surface expression, and signal transduction from the corresponding venus flytrap domain to the seven-transmembrane domain.[62],[63] Immediately following the cysteine-rich domain are 14 amino acids, residues 599 – 612, that have been described as a peptide linker connecting the extracellular domain to the seven-transmembrane domain.[65] Insertion or deletion of amino acids within the peptide linker of the CaR had a negative impact on the cell surface expression of the receptor and abrogated its signaling capacity in response to extracellular ligands.[65] Recent findings have suggested that the CaR has at least two distinct types of motifs mediating dimerization and functional interactions: covalent interactions involving intermolecular disulfide bonds and non-covalent, possibly hydrophobic, interactions.[66]
Figure 6: The amino acid sequence of the human calcium-sensing receptor. The tyrosine residue at the site of signal peptide cleavage is indicated by “X.” The 19 conserved cysteines in the extracellular domain are indicated by filled triangles. The eight conserved N-linked glycosylation sites shown to be important for cell surface expression are indicated by open triangles. Predicted sites of protein kinase C phosphorylation are indicated by asterisks, whereas predicted sites of PKA phosphorylation are indicated by # symbols. The loops within the Venus-flytrap are underlined with dashed lines. The regions of the transmembrane domain that span the membrane are indicated by unbroken lines

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It has been proposed that the extracellular domain of the CaR contains the sites of various ligands thereby initiating conformational changes in the TMD and intracellular domains that initiate signal transduction.[67] Ca 2+ plays the role of first messenger for the CaR [17] and the main importance of extracellular domain of the CaR is highlighted by the fact that it controls the concentrations of extracellular free ionized Ca 2+ [Ca 2+o [Figure 3].[56],[68] Several groups have generated models to identify the Ca 2+-binding pocket. Both Huang and Millerl [69] and Silve et al.[70] have proposed that residues Ser147, Ser170, Asp190, Tyr218, and Glu297 are critical to the binding of Ca 2+ on the extracellular domain of CaR. In separate experiments, both groups performed mutational studies on the receptor that revealed that these five amino acids were positioned in a crevice between the two lobes of the extracellular domain and necessary for full CaR activity.[69],[70] It has been hypothesized that based on the Hill coefficient, three to five Ca 2+ ions can bind cooperatively to the extracellular calcium-sensing receptor.[71],[72],[73] Using the aforementioned strategy, Huang and Miller [69] also identified two additional Ca 2+-binding sites, one in lobe I, containing residues Glu378, Glu379, Thr396, Asp398, and Glu399, and the other in lobe II containing residues Glu224, Glu228, Glu229, Glu231, and Glu232. Therefore, CaR is sensitive to relatively small changes in Ca 2+ in extracellular fluid having a very high concentration of extracellular Ca 2+ (1.1 – 1.3 mM).[68] It has been proposed that the binding of calcium ions at the cleft between lobes in the extracellular domain induces rotation along the dimer interface. Such a conformational change could thus alter the spatial configuration of the membrane spanning portion of the receptor and modulate signal transduction.[74] The N-terminus of ECD also contains a signal peptide cleavage site.[75]

The transmembrane domain

The transmembrane domain (TMD) of the human CaR spans is formed from amino acid residues 613 – 862 and it includes seven hydrophobic regions, referred to as TM1 – TM7 [Figure 3] and [Figure 6].[31],[76] The TMD is central to the transduction of signals from the ECD into a cellular response.[73],[75],[77] It has been hypothesized that ligand binding to the extracellular domain of a CaR leads to conformational changes in TM6 and TM7 and, particularly, a proline residue (P823) in TM6 has been identified as a key structural element involved in calcium signaling.[77],[78],[79] Puzzling, it has been shown that a mutant CaR lacking the ECD also responds to [Ca 2+]o and other polyvalent cations, indicating that TMD also participates in sensing of [Ca 2+]o and other ligands.[76] These data indicate that the actual calcium-sensing domain of the CaR is complex and includes both the ECD and TMD.[44],[53]

In addition to its role in signal transduction, the transmembrane domain is believed to be involved in receptor dimerization through non-covalent interactions.[66] This is consistent with the identification of a consensus dimerization motif for non-covalent hydrophobic interactions in TM5 of the CaR, suggesting that TM5 may be a critical region for receptor dimerization.[80]

The intracellular tail

Unlike both extracellular and transmembrane domains, very few naturally occurring mutations have been identified in the 216 amino acids that comprise the intracellular tail of the CaR.[81],[82] The intracellular tail of the CaR is the least conserved domain between species.[51] However, there remain portions of the intracellular tail that are highly homologous between species, including a membrane proximal region spanning residues 863 – 925 and a region comprised of amino acids 960 – 984. The former has been shown to be essential to the cell surface expression and receptor's ability to initiate signaling cascades, whereas the latter has been shown to be involved in binding to accessory proteins.[82],[83],[84],[85] The nature of an intracellular pathway activated by the CaR depends markedly on the cell type in which the receptor is expressed.[53] Most studies on CaR signalling have been performed in parathyroid cells and human embryonic kidney (HEK-293) cells stably transfected with the CaR. Like other members of GPCRs, CaR acts mainly through G proteins.[73] Experiments using an antibody specific for the CaR phosphorylated at Thr888 revealed that an increase in extracellular Ca 2+ or acute treatment of the CaR with a calcimimetic increased phosphorylation of the CaR at Thr888, an effect ablated by treatment with a calcilytic.[86] It was also observed that after phosphorylation, the Thr888 residue could be dephosphorylated, a process that was inhibited in the presence of the phosphatase inhibitors calyculin or endothall thioanhydride, suggesting that protein phosphatase 2 is responsible for the dephosphorylation of the CaR.[86] This suggests that the CaR is able to activate PKC, which in turn phosphorylates the CaR, leading to inhibition of CaR activity, forming a negative feedback loop. In addition to the PKC phosphorylation sites, there are two predicted protein kinase A (PKA) phosphorylation sites, Ser899 and Ser900 [Figure 3] and [Figure 6], but inhibition studies suggest that PKA has only a minor role in the regulation of the CaR.[87] In human embryonic kidney (HEK-293) and bovine parathyroid cells, the CaR interacts with Gαq/11 subunits of heterotrimeric G proteins, resulting in activation of phospholipases C, A2 and D [Figure 7].[88],[89],[90]
Figure 7: Signal transduction mediated by the extracellular calcium-sensing receptor. For clarity, two G-protein-coupled receptors are shown; this is not meant to imply that the ligands depicted are linked preferentially to a particular intracellular signaling pathway, although see section in text on biased agonism

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The CaR also interacts with a pertussis-toxin-sensitive inhibitory G protein, Gαi, which results in inhibition of adenylyl cyclase (AC).[91] In parallel independent of the G proteins, CaR also activates phosphatidylinositol 4-kinase (PI4K) that catalyses the first step of the inositol lipid biosynthesis by a Rho-dependent mechanism in various cell types.[92],[93],[94] Kifor et al.[95] demonstrated activation of extracellular-signal-regulated kinase (ERK) 1 and 2 in response to CaR agonist treatment in HEK-293 cells and in bovine parathyroid cells. In rat Leydig cancer (H-500) cells expressing CaR, calcium has been shown to activate ERK, p38 MAPK and Jun amino-terminal kinase (JNK).[96] In addition, the CaR has been shown to trans-activate epidermal growth factor receptor (EGFR) in rat Leydig cancer (H-500) cells, HEK-293 cells and human prostate cancer (PC3) cells.[97],[98],[99] Thus, MAPKs can be activated directly by the CaR or indirectly mediated by EGFR transactivation. Activation of MAPKs has been shown to be important for many distal effects of the CaR, such as proliferation, differentiation, regulation of peptide secretion and ion channel activity.[53],[90] Generally, upon changes in [ECF]o, several intracellular signaling pathways are affected, including the cAMP protein kinase A, phospholipase C-protein kinase C, and inositol phosphate pathways.


  Interacting Protein Partners of the Calcium-Sensing Receptor Top


As with all GPCRs families, the CaR signals through interacting with heterotrimeric G proteins. Recently, several other proteins have been also identified that interact with the CaR and influence its signaling characteristics.[69],[84],[100]

Filamin

Filamin A was the first discovered protein interacts with CaR [83],[84] and the sites interaction was residues 962 – 981 of the CaR and amino acids 1566 – 1719 filamin A.[100] Silencing of the filamin A gene in HEK293 cells stably expressing the CaR with small interfering RNA (siRNA) caused a significant decrease in CaR-mediated JNK activation, indicating the necessity of the interaction between the CaR and filamin A for the induction of the JNK signaling cascade by the CaR.[101],[102],[103] Experiments that examined the expression levels of the CaR in M2 cells, a cell line that does not express filamin A, revealed that CaR expression was almost doubled when filamin A was transfected into the M2 cells.[100] Inhibition of CaR expression with CaR antisense cDNA 48 h after the transfection of CaR with or without filamin A resulted in a lower level of CaR expression in cells not expressing filamin A, suggesting that filamin A also protects the CaR against degradation.

Potassium channels

The inwardly rectifying potassium channel 4 family of proteins, consisting of Kir4.1 and Kir4.2, are believed to be involved in the regulation of membrane potential and the recycling of K + for Na +-K +-ATPases.[104] In addition to filamin A, the inwardly rectifying potassium channel Kir4.2 was identified as a binding partner for the CaR intracellular tail.[105] Because filamin A has been shown to interact with the potassium channel Kir2.1,[106] it is possible that filamin A may act as a scaffolding protein that brings the CaR and either Kir4.1 or Kir4.2 together.[73]

Dorfin

Dorfin was identified as another interacting protein partner of the CaR and sites interaction was residues 880 – 900 of the CaR and amino acids 660 – 838 of dorfin.[107] In HEK293 cells transiently expressing the CaR, an increase in the level of dorfin led to an increased rate of CaR degradation. Dorfin-mediated degradation of the CaR via proteasome.[73]

Coimmunoprecipitation experiments indicated that the CaR and dorfin are part of a protein complex that includes the valosin-containing protein, suggesting that the dorfin-mediated degradation of the CaR through the ER associated degradation pathway.[73]

Associated molecule with SH3 domain of signal-transducing adaptor molecule

AMSH is an ubiquitin isopeptidase that is a key regulatory component of endosomal sorting of the epidermal growth factor receptor.[108] A more recent study revealed AMSH as an interacting partner of the CaR.[109] A reduction in CaR expression was observed in response to the increasing levels of transfected AMSH.[110]

β-Arrestins

β-Arrestins are ubiquitously expressed proteins that are involved in the desensitization and internalization of most GPCRs including CaR into clathrin-coated pits.[111] Both β-arrestin 1 and 2 isoforms were found to interact with a region of the CaR intracellular tail between amino acids 877 and 1079 and they reduce the level of CaR activity.[112] Lorenz et al.[113] showed that overexpression of both β-arrestin 1 and 2 had a negative influence on CaR-mediated inositol phosphate production. It is interesting that aside from its important role in receptor desensitization, β-arrestin is one of at least three CaR-interacting protein partners (dorfin, AMSH, and filamin) that promote CaR degradation or stabilization of the receptor.[73] And control of CaR expression by these proteins may be regulated in a tissue-specific and/or situation specific manner.

Receptor activity-modifying proteins

The receptor activity-modifying protein (RAMP) family consists of single-transmembrane spanning proteins that have been shown to affect receptor trafficking, glycosylation, ligand specificity, and second messenger production in several cell types.[114] When the CaR was coexpressed with either RAMP1 or RAMP3, the receptor was delivered to the cell surface, but when coexpressed with RAMP2, the CaR was still not able to be detected at the cell surface.[115]

RAMP3 had a greater influence on the cell surface expression of the CaR than RAMP1, but both had similar effects on receptor trafficking and glycosylation of CaR.[115] Therefore, CaR-interacting partner protein can influence the functionality of the receptor in a tissue-specific manner.


  Unique Features of Extracellular Calcium-Sensing Receptor Top


There are several unique features that set CaR aside from other GPCRs. The CaR is a multifaceted receptor with multiple ligands, such as cations, metabolites, nutrients, and activates a plethora of signalling pathways [Table 1].[116],[117] As the receptor's name suggests, the principal physiological ligand of the CaR is calcium and it is the first G protein-coupled receptor found to have an inorganic ion, Ca 2+, as the first (extracellular) and second (intracellular) messengers.[17] Unique in comparison to many GPCR receptors, which are activated by nanomolar quantities of agonist, the CaR is somewhat resistant to desensitization and allows to detect very small fluctuations in the [Ca 2+]o at very high concentration (1.1 – 1.3 mM).[68] Another feature of the CaR is lack of specificity. Although the main ligand is Ca 2+, CaR is also stimulated in vitro by other divalent cations, such as magnesium and barium, by the trivalent elements, gadolinium and lanthanum, and by polycationic compounds, such as neomycin and spermine.[118] The affinity of cations to the CaR is variable and they rank as follows: La 3+ > Gd 3+ > Ca 2+ = Ba 2+ > Mg 2+.[71],[93] In vivo Mg 2+ is present at a sufficient concentration to activate CaR in an additive fashion and it also been shown to contribute to the regulation of CaR mRNA and protein expression.[17] However, the physiological concentrations of other cations are insufficient to activate CaR under normal circumstances and they contribute to heavy metal toxicity due to high affinity of CaR for them.[119],[120],[121],[122] In addition to these direct agonists, there are several agents, such as L-amino acids, polypeptides and endogenous polyamines, that can act as allosteric activators of the CaR.[53],[123] Amino acids have a greater influence on the CaR mediated mobilization of Ca 2+ from intracellular stores than on CaR-induced phosphorylation of ERK.[124] However, the physiological concentrations of endogenous polyamines, based on order of their potency: spermine > spermidine >> putrescine, are insufficient to activate CaR under normal circumstances.[125] This suggest that a modest rise in polyamines might contribute to CaR signaling physiologically.[126]
Table 1: A list of known agonists and antagonists of the CaR

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Amyloid-β peptide, which is excessively produced in the brain of patients with Alzheimer's disease, has also been shown to stimulate the CaR and is proposed to act on the receptor in a fashion similar to spermine because both molecules have a similar spacing of positive charges.[127] In a screen of a di-and tri-peptide library, the CaR was found to be activated by 46 different γ-glutamyl peptides, including γ-Glu-Cys-Gly and γ-Glu-Val-Gly, which have been categorized as taste-enhancing substances that can elicit the kokumi taste response.[128],[129] There are also many polyvalent aminoglycoside antibiotics that act via the CaR.[130] The order of potency of the aminoglycoside antibiotics tested is as follows: neomycin > tobramycin > gentamicin > kanamycin, suggesting that their efficacies positively correlate with the number of attached amino groups.[131] The affinity of CaR was not only influenced by ionic strength but also changes in pH, which suggests alterations in CaR agonist sensitivity by pH are partially the result of conformational changes to the receptor.[117] Therefore, in many cells and tissues, CaR also acts as a coincidence detector, sensing both changes in extracellular Ca 2+ plus the presence of various allosteric activators including amino acids, polyamines, and/or peptides. Such plasticity with respect to both agonist and signaling outcomes allows CaR to uniquely contribute to the physiology of organs and tissues where it is expressed.[22]


  The Role of Vascular Calcium Sensing Receptor in the Regulation of Vascular Tone and Blood Pressure Top


It is well known that calcium is an important second messenger that acts as an important regulator of vascular contractility.[53] Vascular tone and hence blood pressure are determined by the contractile state of vascular smooth muscle cells (VSMCs) within the blood vessel wall, which is regulated by intracellular calcium concentration ([Ca 2+]i).[132],[133] The major pathways for an increase in myocytes [Ca 2+]i are voltage-dependent Ca 2+ channels (VDCC) and nonselective cation channels at the plasmalemmal membrane or the internal store release channels, i. e., the ryanodine (RyR) and the inositol trisphosphate (IP3R) receptors found in the sarcoplasmic reticulum (SR) membrane.[134],[135] Therefore, vasoconstrictors act through increasing [Ca 2+]i as well as on the apparent calcium sensitivity of the contractile process in VSMCs, whereas relaxing factors have the opposite effect.[133],[134] The vascular endothelium is a cell monolayer that also plays a key role in the regulation of vasomotor tone through the release of vasoconstrictors (endothelin) and through the tonic production and release of NO, PGI2, and EDHF.[136] In contrast to the VSMCs, an increase in endothelial [Ca 2+]i results in vascular relaxation through endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF).[133] These findings suggesting that the nature of calcium signals in endothelium and smooth muscle are fundamentally different.[137],[138] Therefore, an increase in [Ca 2+]i in endothelium or in VSMCs exerts opposing influences on blood vessel diameter for precise regulation of organ and tissue perfusion. However, recent studies suggest that, in addition to its many functions as an intracellular messenger, Ca 2+ may also be an extracellular first messenger through the calcium-sensing receptor (CaR) that are expressed in ECs,[139],[140],[141] VSMCs [142],[143] and on perivascular nerves [144],[145],[146] of blood vessels. In 1997, 4 years after the cloning of the CaR, Bukoski et al.[147] suggested that [Ca 2+]o induces relaxation of the isolated arteries by activating CaR in perivascular nerves, resulting in the release of a nerve-derived hyperpolarizing vasodilator, possibly a cannabinoid. However, Wang and Bukoski reported coronary arteries to contract at [Ca 2+]o levels of 1.5 – 3 mM, and relax only to a small degree with greater [Ca 2+]o concentrations (5 mM).[148] Likewise, in another studies binding of Ca 2+ ( first messenger) to CaR mediate biphasic effects with an initial endothelium-independent vasoconstrictions [149],[150],[151] followed by endothelium-dependent relaxations.[141],[152],[153]

An increase [Ca 2+]o from 1 mM to 6 mM potentiates pre-contracted tone in endothelium-removed vessel segments by affecting Gα protein subunits [17],[30],[154] In contrast, increasing [Ca 2+]o from 1 mM to 6 mM evokes the endothelial membrane hyperpolarization in a functionally intact endothelium by activating of potassium channels.[155],[156] Likewise, it also results in vascular relaxation through endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF)[133],[141] Under physiological condition, CaR-mediate vasorelaxations more dominantly than vasoconstrictions [117],[157] In support of this hypothesis, increasing dietary calcium levels have been reported to have lowering effects on blood pressure in models of hypertension.[158] A calcimimetic, NPS R-568, has been reported to significantly decrease blood pressure in uremic and spontaneously hypertensive rats but not in normotensive rats [159],[160] Furthermore, it is speculated that CaR has non-trivial effects on vascular tone and blood pressure in response to systemic as well as local changes in [Ca 2+]o.[161]


  The Major Proposed Mechanisms of Vasodilation Top


The vascular endothelium CaR activation mostly results in an activation of the G proteins (Gq/11) that causes hydrolysis of membrane phospholipid PIP2 through the stimulation of phospholipase C (PLC) [Figure 8].[162] The stimulation of PLC results in generation of IP3, which promotes the release of Ca 2+ into the cytoplasm by activation of endoplasmic or sarcoplasmic reticulum IP3-gated calcium release channels.[163],[164],[165] Another molecule generated upon PLC activation, diaglycerol, provides the signals for activation of the serine/threonine kinase protein kinase C.[166] Due to the absence of VDCC, activation of PKC causes calcium influx into endothelial cells through transient receptor potential channels (TRPC1, TRPC3, TRPC4, TRPC6, TRPV4, etc.) from the extracellular milieu, which causes feature increase in cytosolic free Ca 2+ within endothelial cells.[156],[167],[168] In parallel, CaR also activates PI4K, which is an enzyme that carries out the first step in inositol lipids biosynthesis, independently of heterotrimeric G proteins, but by a Rho-dependent mechanism [Figure 8].[166] Endothelial calcium ''waves'' and “puffs” (small punctate and local increases of calcium) is an initial step required for endothelium-dependent vasorelaxations.
Figure 8: Calcium-sensing receptor-regulated intracellular signaling pathways in the endothelium of blood vessel

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One consequence of increases in [Ca 2+]i in vascular endothelium,300 – 500 nM, is the activation of calmodulin, which in turn activates the opening small and intermediate conductance calcium-activated potassium channels (SKCa and IKCa) on endothelium [Figure 9].[169] Opening of the small and intermediate conductance calcium-activated potassium channels pore is independent of the membrane potential but strictly depends on [Ca 2+]i. Thus, calcium sensitivity of both channels depends on CaM and the binding of calcium ions to the coupled calmodulin (CaM) induces a conformational change of the complex involving an interlacing of cytoplasmic loops that leads to the channel pore opening.[170],[171] Then after, intracellular K + moves down its electrochemical gradient through the opened SKCa and IKCa channels to the extracellular space and results in the hyperpolarization of the endothelial cells [Figure 9].[136] The hyperpolarization of the endothelial cells is transmitted to the smooth muscle cells by direct electrical coupling through myoendothelial junctions and/or by the accumulation of potassium ions in the intercellular myoendothelial space.[172]
Figure 9: Roles of SK and IK channels in the regulation of vascular function

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An efflux of K + in the lumen of the blood vessel from endothelium would be washed away by the flowing blood and be most likely without physiological consequences. However, the membrane potential hyperpolarization induced by SKCa and IKCa channels opening would further increase calcium influx in endothelial cells by increasing the electrochemical gradient for calcium.[133] An efflux of K + toward the abluminal side can accumulate in the intercellular space between endothelial and smooth muscle cells and when it reach sufficient levels (from ~4 mM to 12 mM) there will be activation of both inwardly rectifying potassium channel (Kir) and Na +/K + ATPase in the membrane of the vascular smooth muscle on the smooth muscle cells in the immediate vicinity of the endothelial cells releasing K +.[173],[174],[175] A unique feature of Kir channels is the effect of extracellular potassium on its gating. A moderate increase in potassium concentration, in the range of 1 to 15 mM, enhances potassium efflux through Kir at physiologically relevant potentials.[176],[177] Whereas, at the expense of ATP, Na +/K + ATPase exchanges three intracellular Na + s for two extracellular K + s.[178] Thus, the net result is loss of positively charged K + from vascular smooth muscle cells, which results in hyperpolarization and subsequent dilation of the artery [Figure 10].[169],[179],[180],[181],[182],[183] It is also possible that other K + channels such as Kv7 and KATP channels expressed in VSMCs may be involved in mediating CaR induced vasorelaxations.[184],[185]
Figure 10: Mechanism of K+ acting as endothelium-derived hyperpolarizing factor

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Although it has been known that gap junctions, the minute tunnels with internal diameter of 1.5nm, exist between endothelial cells and between vascular smooth muscle cells, they also seem to exist between endothelium and vascular smooth muscle (myoendothelial gap junctions).[186],[187],[188],[189] These myoendothelial gap junctions are thought to have a major role in electrical spread of hyperpolarization from the endothelial cells to the smooth muscle cells through myoendothelial gap junctions.[190],[191] Therefore, K + could be an EDHF or contribute to the mechanism of EDHF-mediated responses. In addition, it is well recognised that SKCa and IKCa channels that are expressed in ECs have pivotal roles in mediating endothelium-derived hyperpolarisations which couple to relaxation of VSMCs.[192],[193],[194],[195] In addition, the endothelial CaR can also modulate the diameter of blood vessels via another type of endothelium derived hyperpolarizing factor (EDHF).[136] The endothelial CaR activation via Gq subunits of heterotrimeric G proteins activation, also result in activation of phospholipases A2 (PLA2) that translocated from the cytoplasm to cellular membranes.[196] There is also evidence that CaR-induced activation of ERK can lead to the phosphorylation and activation of PLA2.[95] However, PKC activity is only partially responsible for CaR-mediated activation of PLA2.[162] Because PLA2 is constitutively active, the translocation to the membrane places it in contact with the phospholipid substrate and promotes the release of arachidonic acid within the cell.[164],[165],[197],[198]

The liberated arachidonic acid has several possible fates. It either reincorporated into plasma membrane phospholipids, where it can act as a messenger or metabolized further by cyclooxygenase, epoxygenase, lipoxygenase, or Ω-hydroxylase [Figure 11].[144],[145],[146]
Figure 11: Several possible fates of arachidonic acid

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The first mechanism proposed for EDHF dilations involves the metabolism of arachidonic acid through the epoxygenase pathway to form epoxyeicosatrienoic acids (EETs).[199],[200],[201],[202] The EETs diffuse from the endothelium to the vascular smooth muscle and activate large conductance calcium-activated K + channel (BKCa) that results in further K + efflux from the smooth muscle cell and causes VSMC hyperpolarization and vasorelaxation [Figure 12].[203],[204],[205] In addition, the opening of the large-conductance Ca 2+-activated K + channel (BKCa) also promotes the closure of VDCC and thus opposing vasoconstriction.[133] Additionally, EETs activate smooth muscle vanilloid transient receptor potential channel (TRPV4), which increase the frequency of calcium sparks and subsequently that of spontaneous transient outward currents. The implication is that BKCa channels are clustered in a plasmalemmal region close to the RyR calcium SR release channels and so are exposed to a high concentration of store-released calcium early after SR calcium channel opening.[206],[207]
Figure 12: Mechanism of epoxyeicosatrienoic acid acting as endothelium-derived hyperpolarizing factor

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In arterial smooth muscle and intact arteries, Ca 2+ sparks are observed just under the cell membrane consistent with a predominant subsarcolemmal localization of the RyR Ca 2+ release channels in the sarcoplasmic reticulum.[208],[209] This EET-dependent activation of a calcium-signaling complex (TRPV4-ryanodine receptors-BKCa) hyperpolarizes and relaxes the smooth muscle cells.[210] In addition, EETs may also regulate the activity of endothelial SKCa and IKCa.[211] Although EETs activate BKCa through a G protein–signaling cascade, the existence of a specific cell membrane receptor(s) for EETs that stimulate production of cAMP and activate protein kinase A that hyperpolarization through facilitate opening of both BKCa and KATP in vascular smooth muscle has been also established [Figure 12].[212],[213]

Furthermore, metabolism of arachidonic acid through the lipoxygenase pathway results in released of 12-(S)-HETE from the endothelium that also activates BKCa on the smooth muscle cells.[214],[215],[216] Prostacyclin is the major metabolite of arachidonic acid produced by cyclooxygenase in endothelial cells.[217] It activates IP3 receptors on vascular smooth muscle and, in most normal arteries, produces relaxation. Depending on the artery and/or the species, a hyperpolarization can occur, which involves the opening of one or more of types of potassium channels.[218] Thus, ATP-sensitive potassium channels (KATP), large conductance calcium-activated potassium channels (BKCa), inwardly rectifying potassium channels (Kir) and/or voltage activated potassium channels (KV) can be associated with the prostacyclin-induced relaxation.[219] In addition to transmitting state of hyperpolarization, myoendothelial gap junctions can also allow passage of small water soluble molecules (<1,000 Da) including cyclic guanosine monophosphate, inositol triphosphates, and inorganic ions, thus providing smooth muscle cell relaxation.[220],[221],[222],[223] The main source of NO• in the vasculature is the microvascular endothelium, from where it can contribute to cGMP activation in vascular smooth muscle cells and thus influence vascular reactivity.[224],[225] Endothelium-derived NO is synthesized by endothelial nitric oxide synthase (eNOS) which converts semi-essential amino acid L-arginine to L-citrulline and NO [Figure 13].[226],[227],[228],[229] The eNOS stimulation is due to the activation of calmodulin, as consequence of increases in [Ca 2+]i in vascular endothelium.[230] Thus, high [Ca 2+]i-induced eNOS upregulation is indeed CaR mediated.
Figure 13: Biosynthetic pathway for nitric oxide. NADPH is an essential cofactor for this reaction and L-NAME acts as an inhibitor of (at least) two steps in the pathway

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NO regulates vascular tone by different signaling pathways.[231],[232],[233] First, the classic NO-sGC-cGMP pathway vasodilator effects [Figure 14].[234],[235],[236] The NO• formed diffuses to underlying vascular smooth muscle, where its actions include stimulation of soluble guanylate cyclase (sGC), which induces formation of cyclic guanosine monophosphate (cGMP).[237],[238],[239] Cyclic GMP activates protein kinase G, which prevents the calcium influx from VDCC and calcium release mediated by IP3R.[233],[234] PKG also acts on sarco/endoplasmic reticulum calcium ATPase (SERCA) to promote the reuptake of cytosolic calcium into the sarcoplasmic reticulum (SR) and the opening of large conductance calcium activated potassium channel (BKCa) activation in vascular smooth muscle cells [Figure 14].[240],[241],[242] As a result, the intracellular concentration of calcium decreases and calmodulin is inactivated which no longer able to activate Myosin light chain kinase (MLCK). Calcium depletion also increases the activity of myosin light chain phosphatase (MLCP). The actin-myosin cross-bridge is broken and smooth muscle relaxation ensues.[243],[244],[245] Secondly, independent of the classic NO-sGC-cGMP pathway, NO• can undergo reactions, in the presence of an electron acceptor, with cysteine thiol containing compounds to form biologically active S-nitrosylated molecules.[246],[247],[248] Like PKG, NO• derived peroxynitrite (ONOO•) can directly acts on sarco/endoplasmic reticulum calcium ATPase (SERCA) to enhance the reuptake of cytosolic calcium into the sarcoplasmic reticulum by S-glutathiolation [Figure 14].[249] The S-nitrosylated molecules can also regulates the expression and functions of G protein coupled receptors (GPCRs).[250],[251] For instance, NO and S-nitrosothiols modulate the activity of GPCR kinase 2 (GRK2) which phosphorylates β-adrenoceptors and induce receptor desensitization and internalization to prevent the loss of β-adrenergic signaling in blood vessels to induce vasodilatation.[252],[253],[254] Likewise, S-nitrosoglutathione inhibits α1-adrenoceptor-mediated vasoconstriction and ligand binding.[255] In addition, S-nitrosylation of cysteine 289 of the AT1 receptor decreases its binding affinity for angiotensin II.[256] Cytosolic β-arrestin binding to CaR and GRK-phosphorylated GPCRs sterically impedes the interaction of G-proteins with activated GPCRs, resulting in GPCR signaling termination.[257],[258],[259] Also, β-arrestin 2, can be S-nitrosylated on cysteine 410 by endogenous NO and S-nitrosogluthathione, which promotes binding of β-arrestin 2 to clathrin heavy chain/β-adaptin, thereby accelerating receptor internalization and induces vasorelaxation.[233],[260]
Figure 14: Regulation of vascular tone by nitric oxide

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In generally, NO can also induces vasorelaxation by facilitating formation ofS-nitrosylated that has many functions:- firstly:-S-nitrosylation increases the activity of SERCA, which accelerates calcium depletion and induces relaxation. Secondly, GPCR can be directly S-nitrosylated by NO, which impedes the binding of ligands for the receptor or G-protein coupling. Thirdly, S-nitrosylation of GRK2 prevents the desensitization and internalization of β-adrenoceptors. Fourthly, S-nitrosylation of β-arrestin 2 increases receptor internalization.

Finally, the recent evidence suggests that the CaR is expressed in JG cells and that activation of the receptor decreases renin secretion, as well as Ang II, by suppressing the activity of the Ca 2+-inhibitable type V adenylate cyclase (AC-V),[261] and through activation of the PLC/IP3 pathway and the ryanodine receptor that results in stimulation of calcium/calmodulin by phosphodiesterases.[262],[263],[264]


  Conclusion Top


Calcium is a crucial signal molecule that acts via changes in intracellular Ca 2+ levels through the actions of calcium channels and pumps. However, it is now well known that calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular Ca 2+ concentration, the calcium sensing receptor (CaR). It consists of three structural domains – a large extracellular domain in the N-terminal portion of the receptor, a seven-transmembrane region that anchors it in the plasma membrane and an intracellular carboxyl terminal tail with regulatory proteins phosphorylation sites. CaR function as a disulfide-linked dimer that likely can be driven to distinct active conformations by various Ca 2+ plus modulator combinations, which can drive preferential coupling to divergent signaling pathways. Binding of extracellular Ca 2+ or other ligands to the ECD of CaR triggers a number of intracellular signalling systems like the activation of Gαq proteins result in stimulation of phospholipase C, which leads to the generation of second messengers (DAG and IP3) and intracellular Ca 2+ release; inhibition of adenylate cyclase activity result in suppression of intracellular cAMP; activation of PKC and MAPK – p38, JNK/SAPK and MEK1/ERK1,2 etc., In addition to the G proteins, the CaR binds the scaffolding protein filamin A, G-protein coupled kinases (GRKs) and β-arrestins, which add the complexity of the downstream signalling mechanism of the receptor. Therefore, it is not surprising that CaR is involved in the regulation of such diverse processes as hormone secretion, gene expression, ion channel activity, modulation of inflammation, proliferation, differentiation and apoptosis. It is now evident that the presence of the CaR in animal blood vessels of many types, in perivascular nerves, endothelial cells and vascular smooth muscle cells, suggests it may regulate the vascular tone. This could provide a mechanism for the almost 100-year-old observation that [Ca 2+]o induces vasodilation. In particular, these novel results indicate that stimulation of CaRs induces endothelium-dependent vasorelaxations which are mediated by opening of the Ca 2+-sensitive potassium channels, NO production and inhibit renin production. All together, these results indicate that the CaR may have a physiological role in the modulation of blood pressure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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