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, 107 (41), 17791-6

Calcium-sensing Receptor Is a Physiologic Multimodal Chemosensor Regulating Gastric G-cell Growth and Gastrin Secretion

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Calcium-sensing Receptor Is a Physiologic Multimodal Chemosensor Regulating Gastric G-cell Growth and Gastrin Secretion

Jianying Feng et al. Proc Natl Acad Sci U S A.

Abstract

The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Mouse antral gastrin-producing cells express CaR protein. Dual immunohistochemistry for CaR and gastrin in CaR WT (CaR+/+PTH−/−; Top) and CaR-null (CaR−/−PTH−/−; Middle) gastric antrum. Control (Bottom) immunostaining of CaR-null gastric antrum in the absence of primary antibody for gastrin; 5-μm sections of formalin fixed paraffin embedded gastric antrum from fasted mice were double immunostained for gastrin and CaR using monoclonal anti-human CaR and rabbit polyclonal anti-human gastrin. CaR and gastrin expression were detected with highly absorbed goat anti-mouse Alexa 488 and goat anti-rabbit Alexa 594 secondary antibodies, respectively. Immunofluoresence of representative images chosen from multiple sections was obtained using a Zeiss LSM510 confocal microscope.
Fig. 2.
Fig. 2.
Loss of gastrin response to gavaged secretagogues in CaR-null mice. Basal (open bars) and stimulated (filled bars) plasma gastrin measured by RIA in CaR WT (CaR+/+ PTH−/−), heterozygous (CaR+/− PTH−/−), and null (CaR−/− PTH−/−) littermates after an overnight fast (0 min; A) and after gavage (30 min) of either (B) Ca2+ gluconate (100 mM), (C) peptone (8%), (D) l-phenylalanine (100 mM), or (E) Hepes buffer (150 mM, pH 7.0). (A) *P < 0.05 vs. CaR−/− PTH−/− (n = 5 mice). (B) **P < 0.01 vs. basal (n = 6 mice). (C) *P < 0.05 vs. basal (n = 5 mice). (D) *P < 0.05 vs. basal (n = 7 mice).
Fig. 3.
Fig. 3.
CaR-specific agonist and antagonist stimulate and inhibit gastrin secretion, respectively, in CaR WT mice. (A) Gastrin stimulation by CaR-specific agonist, cinacalcet (100 mg/kg by gavage. **P < 0.01 vs. vehicle (n = 9 mice). (B) Inhibition of gavaged peptone-stimulated gastrin by the CaR-specific antagonist, NP-S2143 (1 mg/kg, i.v., 30 min before gavage) at a dose shown to significantly stimulate PTH secretion compared with vehicle. *P < 0.05 vs. vehicle (n = 9 mice). Results are expressed as the percent change (mean ± SEM) in secretion relative to basal.
Fig. 4.
Fig. 4.
Inhibition of GRP has no significant effect on peptone-stimulated gastrin secretion. WT (C57BL/6) mice were fasted overnight, i.v. administered with either BIM 26226 or saline control, and immediately gavaged with peptone. Plasma gastrin was measured by RIA just before (open bars) and 30 min after (closed bars) peptone gavage. *P < 0.05, pre- vs. postgavage (ns, peptone plus saline vs. peptone plus BIM 26226; n = 6 and 10 mice for saline and BIM 26226, respectively). ns, nonsignificant.
Fig. 5.
Fig. 5.
CaR-null (CaR−/−PTH−/−) mice have markedly reduced antral G cells and stomach gastrin content at age 60 d. (A) Immunostaining for gastrin in representative sections of antrum. (B) Average number of immunoreactive G cells per gland. Data are the mean number of G cells per gland ± SEM. ***P < 0.001 vs. CaR−/−PTH−/− (n = 50 glands/genotype). (C) Whole-stomach gastrin content. Data are the mean for the extraction of gastrin from the whole stomach ± SEM. ***P < 0.001 vs. CaR−/−PTH−/− (n = 5 stomachs/genotype).
Fig. 6.
Fig. 6.
CaR-null mice progressively lose gastrin-producing G cells between 30 and 90 d of age. (A) At the indicated age, gastric antral cryosections were prepared for gastrin immunohistochemistry for CaR-null (CaR−/−PTH−/−) and WT (CaR+/+PTH−/−) littermates. Representative images are presented from among multiple sections obtained from at least three mice for each genotype. (B) Average number of immunoreactive G cells per gland. Data are the mean number of G cells per gland ± SEM. ***P < 0.001, WT (CaR+/+PTH−/−, open bars) vs. knock out (CaR−/−PTH−/−, closed bars; n = 10 glands/age group).

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