Calcium-Sensing Receptors Mediate Amino Acid Signals From the Liver to Islet Alpha Cells

How does the body defend itself against high plasma levels of amino acids? New work identifies amino acid–sensing calcium-sensing receptors on pancreatic islet α-cells as a key component of the mechanism.

As endocrinologists, we often ask: are the serum levels of hormones abnormal, and/or are there disturbances of receptor expression or function? These questions apply in diverse clinical contexts, whether the hormones are peptides, steroids, or small organic molecules—and, in general, receptors select precisely for one specific chemical species or, in some cases, a discrete family of closely-related molecules. It was expected that receptors for nutrients, which interact with the production and release of hormones, would act in a similar way. They don’t.

Working with Dr. Edward Brown of the Brigham and Women's Hospital (Harvard), one of us (A.C.) hypothesized that class C G protein–coupled receptors (GPCRs) might be different: that these receptors might be sensitive to more than one class of nutrient/chemical activator and might thus have broader roles in biology. Noting that one of these receptors, the calcium-sensing receptor (CaSR), selected for the divalent cation Ca²⁺ and that several of its closest relatives, including various subtypes of metabotropic glutamate receptors and GABA_B receptors selected for the amino acid glutamate or the glutamate analog, γ-aminobutyrate, respectively, it seemed plausible that one or more of the glutamate receptors might be sensitive to divalent cations including Ca²⁺ (they are!) and that the CaSR might respond to one or more amino acids. In collaboration with Ed's colleague Steve Quinn, we tested the effects of all 20 genetically encoded amino acids and, in the presence of physiological levels of extracellular Ca²⁺, found that numerous amino acids from various subclasses were robust activators of the CaSR (1). Effective amino acids included aromatics such as phenylalanine and tryptophan, which are known for releasing gastrointestinal hormones such gastrin and cholecystokinin, and aliphatics, including alanine, glutamine, and cysteine, with a wide spectrum of effects on systemic metabolism. Somewhat surprisingly, the receptor responded only poorly to glutamate, to cationic amino acids such as arginine, and to branched-chain amino acids such as leucine.

This pattern of amino acid selectivities places the CaSR in a particular niche—but what exactly is that “niche” and what is the scope of the resulting biology? Could it modulate mineral metabolism or amino acid metabolism or both? The receptor selected for natural L-isomers over D-amino acids, and a specific binding site was confirmed in the receptor's canonical bi-lobed cleft (2). It did not take long for other groups to report that other class C GPCRs, including a taste receptor heterodimer (Tas1R₁/Tas1R₃), were promiscuous amino acid sensors (3).

Consistent with its pharmacology, the CaSR is expressed widely in entero-endocrine cells of the gastrointestinal tract and was indeed found to mediate amino acid-dependent stimulation of gut hormone secretion (4). It was also found to couple protein metabolism to mineral metabolism via amino acid-dependent inhibition of parathyroid hormone secretion and stimulation of calcitonin secretion (5).

There has been doubt, however, as to whether the CaSR participates in the control of whole-body protein and/or amino acid metabolism. This question is now resolved decisively in the affirmative by the work of Gong et al: “Hyperaminoacidemia induces pancreatic α-cell proliferation via synergism between mTORC1 and CaSR-G_q signaling pathways” (6). Prior to this study, the importance of glucagon in controlling hepatic amino acid breakdown was established in mice null for either glucagon or the glucagon receptor. Such transgenic mice develop hyperaminoacidemia and, in turn, pancreatic islet α-cell hyperplasia. Previously the amino acid–sensing mechanism in islet α-cells was found to be dependent on mTORC1-dependent upregulation of the glutamine transporter SLC38A5. Crucially, however, mTORC1 activation alone, while sufficient to drive increases in α-cell size (hypertrophy), could not drive increases in cell number. Gong et al hypothesized that a receptor for extracellular amino acids was required and screened the CaSR, taste receptor heterodimers, and another amino acid sensor GPRC6A for roles in hyperaminoacidemia-induced hyperplasia. Only the CaSR was required in both zebrafish and mouse models. Indeed, the CaSR acting via G_q/11 supported hyperaminoacidemia-induced proliferation, promoted mTORC1 activation, worked synergistically with mTORC1, and upregulated the glutamine transporter.

Thus, the new work demonstrates that a nutrient-sensitive surface receptor, a class C GPCR, monitoring the extracellular L-amino acid concentration on islet α-cells plays a key role in whole-body protein–amino acid metabolism and contributes to the liver-dependent defense against hyperaminoacidemia. It does so by stimulating α-cell proliferation acting, in turn, to promote glucagon production and hepatic glucagon signaling, to drive amino acid breakdown via the urea cycle. It underscores recent understandings that persistent elevations in the serum glucagon level and hepatic glucagon signaling act primarily, not to raise plasma glucose levels, but to lower plasma amino acid levels and, in the context of glucagonoma, to lower plasma amino acid levels below the normal range (7).

From another clinical perspective, glucagon receptor antagonists have been proposed as a new form of therapy for diabetes, acting to lower plasma glucose levels. The new work provides further evidence that glucagon receptor antagonists will raise plasma amino acid levels and induce islet α-cell hyperplasia with the potential for tumor development, and also induce high serum glucagon levels. These effects and their consequences require careful study.

The work raises further questions: 1) Do the CaSR and/or glucagon defend against hyperaminoacidemia in other ways eg, by suppressing protein appetite? 2) Does the CaSR mediate amino acid-dependent signals for the growth or maintenance of other tissues?

A key component of the body's defense against low dietary protein is mediated by fibroblast growth factor 21 (FGF21), whereby low dietary protein powerfully stimulates FGF21 production and increases serum FGF21 levels to switch on “protein appetite” via actions on central feeding centers (8). The control system newly described by Gong et al provides another key component of the homeostatic mechanism. Solving the mechanisms that underpin the defenses against protein/amino acid deficiency, on the one hand, and protein/amino acid excess, on the other, now seem tantalizingly close.

Abbreviations

CaSR

calcium-sensing receptor

GPCR

G protein–coupled receptor

Funding

NHMRC Australia Grant GNT1149976, S.J. Simpson and colleagues, Nutrition and Complexity 2019-2023, AUD12, 981,420.

Disclosures

A.D.C. is a member of the Board of Bowel Cancer Research Foundation (unpaid role). S.J.S. is Executive Director of Obesity Australia (unpaid role) and a member of the Board of Heart Research Australia on behalf of the University of Sydney (unpaid role).