Commentary Article - (2023) Volume 0, Issue 0
Received: 16-Aug-2023, Manuscript No. IPP-23-17321; Editor assigned: 18-Aug-2023, Pre QC No. IPP-23-17321 (PQ); Reviewed: 01-Sep-2023, QC No. IPP-23-17321; Revised: 08-Sep-2023, Manuscript No. IPP-23-17321 (R); Published: 15-Sep-2023, DOI: 10.51268/1590-8577-23.S8.004
Glucagon was discovered 100 years ago by Kimball and John due to its potent glucogenic activity [1]. Aside from promoting glucose production using glucogenic Amino Acids (AA) and other substrates, glucagon is also a crucial hormone in stimulating Amino Acids (AA) catabolism by activating ureagenesis in the liver [2-4]. Loss of Glucagon Receptor (GCGR) function results in marked increase of plasma AA concentration (hyper aminoacidemia) from zebrafish to humans. Hyper aminoacidemia in turn promotes compensatory proliferation of glucagon-producing α cells [5-8], revealing a liver-α cell axis that tunes α cell mass and function with glucagon signaling in the liver [9,10]. How hyperaminoacidemia promotes α cell proliferation specifically is not well understood.
Not surprisingly, previous studies have identified an essential role for the AA sensor mTORC1 in hyperaminoacidemia-induced α cell proliferation [8]. In zebrafish and mice, the small neutral AA transporter Slc38a5, or SNAT5, is also important for the compensatory α cell proliferation. However, genetic activation of mTORC1 alone in mouse α cells failed to induce α cell hyperplasia in neonatal islets. Although increased proliferation was detected in adult mice due to impaired GCGR function in the liver, the increase is significantly lower than in Gcgr- /- islets [11]. Thus, other cell intrinsic signals may also be involved in the compensatory α cell proliferation. Identification of the additional pathways is therefore important for understanding how hyperaminoacidemia stimulates α cell proliferation. Our recent study uncovered that the AA-sensitive Calcium Sensing Receptor (CaSR), via Gq signaling pathway, synergized with mTORC1 in promoting α cell proliferation. Notably, co-activation of Gq and mTORC1 is sufficient for inducing pancreatic α cell proliferation in the absence of hyperaminoacidemia [12].
CaSR is a class C G-protein-coupled Receptor (GPCR) that senses L-AA and Ca2+ among other endogenous ligands [13,14]. CaSR is expressed not only in calcitropic tissues (eg. parathyroid glands, kidney and breast), but also in noncalcitropic tissues including enteroendocrine and pancreatic islets [13]. In the pancreatic islets, CaSR is highly expressed in α and β cells, and regulates the secretion of these pancreatic endocrine cells [15,16]. Importantly, CaSR also regulates cell proliferation, as its mutation or aberrant activation is associated with various cancers and alters pancreatic islet mass [17-19]. These clues advanced CaSR as a candidate in mediating hyperaminoacidemia- induced pancreatic α cell proliferation.
In our study, we first identified that CaSR is cell-autonomously required for hyperaminoacidemia-induced α cell proliferation in zebrafish and mouse islets [12]. CaSR couples to multiple heterotrimeric G-proteins (Gq/11, Gi/o, or G12/13) to regulate intracellular signal transduction cascades [20,21]. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in zebrafish, we found that CaSR signals through Gq not Gi, to mediate α cell proliferation. Importantly, co-activation of Gq and mTORC1 was sufficient for α cell proliferation in normal aminoacidemia [12]. CaSR-Gq cascades induce elevated cytosolic calcium concentrations and activate the Mitogen Activated Protein Kinase (MAPK) pathway, which ultimately phosphorylate and activate ERK1/220. Our study also demonstrated that Mek1/2-ERK1/2 was the downstream effector of CaSR-Gq. Unexpectedly, we also found that CaSR-Gq-ERK1/2 was required for mTORC1 activation in mediating hyper aminoacidemia-induced α cell proliferation [12]. We therefore identified the two major necessary and sufficient pathways activated by hyperaminoacidemia to promote α cell proliferation. As such, we revealed a previously unknown physiological role of CaSR in the liver-α cell axis.
Our recent study also raises further questions: 1. What is the exact interplay between CaSR-Gq-ERK1/2 and mTORC1 during hyper aminoacidemia inducing α cell proliferation? 2. Why α cell is specifically sensitive to hyper aminoacidemia? We believe the upcoming studies by us or others will answer these questions soon.
We thank Drs. Alvin Powers and Danielle Dean for collaboration and members of the Chen lab for discussion. This work is supported by and NIH grant (R01DK117147) to WC.
Citation: Gong Y, Chen W. CaSR-Gq-ERK1/2: A New Addition to the Liver-a Cell Axis in Hyperaminoacidemia-Triggered a Cell Proliferation. JOP. J Pancreas. (2023) 23:7-8.
Copyright: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
