pH Sensing by the Calcium-sensing Receptor

Abstract

The calcium-sensing receptor (CaR) is activated by small changes in the ionic extracellular calcium concentration (Ca o ) within the physiological range, allowing the parathyroid gland to regulate serum Ca o ; however, the CaR is also distributed in a number of other tissues where it may sense other endogenous agonists and modulators. CaR agonists are polycationic molecules, and our previous studies suggest that charged residues in the extracellular domain of the CaR are critical for receptor activation through electrostatic interactions. Therefore, pH could also potentially modulate CaR activation by its polycationic agonists. Changes in the concentration of extracellular H ؉ substantially altered the activation of the CaR by Ca o and other CaR agonists. The effects of external pH on the CaR's sensitivity to its agonists were observed for both acidic and basic deviations from physiological pH of 7.4, with increases in pH rendering the receptor more sensitive to activation by Ca o and decreases in pH producing the converse effect. At pH values more acidic than 5.5, CaR sensitivity to its agonists showed some recovery. Changes in the intracellular pH could not account for the effects of external pH on CaR sensitivity to its agonists. Other G-proteincoupled receptors, which are endogenously expressed in human embryonic kidney 293 cells, showed little change in activity with alterations in external pH or effects opposite those found for the CaR. Extracellular pH directly alters the CaR in the case of Ca o and Mg o activation; however, the charges on many organic and inorganic agonists are pH-dependent. Activating CaR mutations show reduced pH o modulation, suggesting a molecular mechanism for increased CaR activity at physiological pH o . Several CaR-expressing tissues, including regions of the stomach, the kidney, bone, and the brain, could potentially use the CaR as a sensor for pH and acid-base status.

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

“…In fact, recent studies with isolated rat G cells show decreased gastrin release after a drop in pH from 7.4 to 5.5 (30). Furthermore, the CaR response to Ca 2+ is significantly enhanced with increasing pH (12) within the range of pH 5.5-9 in transfected HEK293 cells (12) and above pH 7.5 in Xenopus oocytes (33). Therefore, to determine whether the Gcell CaR could sense increasing gastric luminal pH, the acidic gastric mucosa of fasting mice was neutralized with Hepes buffer (pH 7).…”

“…Although there have been several in vitro-based studies in either a variety of heterologously transfected cell systems (11)(12)(13) or acutely isolated primary cell cultures (14) that support the role of CaR as a multimodal sensor regulating both Ca 2+ and non-Ca 2+ homeostatic cell systems, there has not been any in vivo physiologic evidence confirming this proposed role.…”

Milk Alkali Syndrome and the Dynamics of Calcium Homeostasis

“…In the remainder of the small and large intestines, the role of the CaSR on intestinal calcium absorption is not known, but it may regulate fluid secretion at these sites (76). Whether systemic metabolic alkalosis, which has been shown to enhance directly the activity of the CaSR in the kidney (71,72), has a similar effect on the CaSR in the intestinal epithelial cell is not known. If it does, then it could have important effects on intestinal calcium absorption.…”

“…The precise role, if any, for modulation of the CaSR by pH in the TALH is unclear. It has been postulated that the CaSR may serve as an extracellular pH sensor in some tissues (71). Because the NKCC also transports NH 4 ϩ , pH regulation of the CaSR theoretically could serve to regulate an important step in the excretion of acid and regeneration of bicarbonate.…”

“…Acute metabolic alkalosis has been shown to suppress PTH secretion in animal studies (70). In vitro studies have shown that metabolic alkalosis increases the sensitivity of the CaSR to extracellular calcium (71,72), which in turn would inhibit PTH secretion. If chronic metabolic alkalosis also suppresses PTH secretion, then it could decrease bone turnover and thereby decrease the capacity for bone buffering of calcium.…”