The following text describes a protein:
Function:
G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis. Senses fluctuations in the circulating calcium concentration: activated by elevated circulating calcium, leading to decreased parathyroid hormone (PTH) secretion in parathyroid glands (By similarity). In kidneys, acts as a key regulator of renal tubular calcium resorption (By similarity). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G-proteins) and modulates the activity of downstream effectors. CASR is coupled with different G(q)/G(11), G(i)/G(o)- or G(s)-classes of G-proteins depending on the context. In the parathyroid and kidney, CASR signals through G(q)/G(11) and G(i)/G(o) G-proteins: G(q)/G(11) coupling activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers, while G(i)/G(o) coupling mediates inhibition of adenylate cyclase activity. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation. Acts as an activator of the NLRP3 inflammasome via G(i)/G(o)-mediated signaling: down-regulation of cyclic AMP (cAMP) relieving NLRP3 inhibition by cAMP (By similarity). Acts as a regulator of proton-sensing receptor GPR68 in a seesaw manner: CASR-mediated signaling inhibits GPR68 signaling in response to extracellular calcium, while GPR68 inhibits CASR in presence of extracellular protons (By similarity).
Subcellular Localization:
Cell membrane; Multi-pass membrane protein.
Domain:
The extracellular regions of the homodimer interact in a side-by-side fashion while facing opposite directions. Each extracellular region consists of three domains, LB1 (ligand-binding 1), LB2 and CR (cysteine-rich). The two lobe-shaped domains LB1 and LB2 form a venus flytrap module. In the inactive configuration, the venus flytrap modules of both protomers are in the open conformation associated with the resting state (open-open) and the interdomain cleft is empty. In addition, each protomer contains three anions, which reinforce the inactive conformation, and one calcium ion. In the active configuration, both protomers of extracellular regions have the closed conformation associated with agonist-binding (closed-closed). The ligand-binding cleft of each protomer is solely occupied by an aromatic amino-acid. Calcium is bound at four novel sites, including one at the homodimer interface. Agonist-binding induces large conformational changes within the extracellular region homodimer: first, the venus flytrap module of each protomer undergoes domain closure. Second, the LB2 regions of the two protomers approach each other, resulting in an expansion of the homodimer interactions involving LB2 domains. Third, the CR regions of the two subunits interact to form a large homodimer interface that is unique to the active state. The CR regions are brought into close contact by the motion involving LB2 since the two domains are rigidly associated within each subunit; G-protein recognition is mediated by the intracellular loop 2 (ICL2) and the C-terminus, which contribute differentially towards the binding of the 2 G-protein subtypes G(q)/G(11) and G(i)/G(o), resulting in distinct CASR-G-protein interfaces. The C-terminus confers selectivity for G(q)/G(11), while it contributes less to G(i)/G(o)-coupling. The C-terminus adopts opposing orientations for G(q)/G(11) and G(i)/G(o)-coupling; The arginine-rich retention motif inhibits localization to the plasma membrane, possibly by promoting interaction with 14-3-3 proteins. Phosphorylation at Ser-893 by PKC and Ser-900 by PKA relieve inhibition and promote plasma membrane localization.
Sequence:
MALYSCCWILLAFSTWCTSAYGPDQRAQKKGDIILGGLFPIHFGVAVKDQDLKSRPESVECIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLDEFCNCSEHIPSTIAVVGATGSGISTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEKIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGRIWLASEAWASSSLIAMPEYFHVVGGTIGFGLKAGQIPGFREFLQKVHPRKSVHNGFAKEFWEETFNCHLQEGAKGPLPVDTFLRGHEEGGARLSNSPTAFRPLCTGEENISSVETPYMDYTHLRISYNVYLAVYSIAHALQDIYTCIPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTSNMGEQVTFDECGDLAGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINDEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACDKCPDDFWSNENHTSCIAKEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLCCFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWGLNLQFLLVFLCTFMQIVICAIWLNTAPPSSYRNHELEDEIIFITCHEGSLMALGFLIGYTCLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIAILAASFGLLACIFFNKVYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRQRSSSLGGSTGSTPSSSISSKSNSEDPFPQQQPKRQKQPQPLALSPHNAQQPQPRPPSTPQPQPQSQQPPRCKQKVIFGSGTVTFSLSFDEPQKTAVAHRNSTHQTSLEAQKNNDALTKHQALLPLQCGETDSELTSQETGLQGPVGEDHQLEMEDPEEMSPALVVSNSRSFVISGGGSTVTENMLRS