Stimulatory Transducing Systems in Pancreatic Islet Cells^a

Abstract

We have determined the cellular distribution of different alpha subtypes of G proteins and adenylyl cyclase (AC) isoforms in endocrine, exocrine, and established pancreatic cell lines. VIP, PACAP, and tGLP-1 receptor proteins are expressed to varying extents in A and B cells, whereas the expression of G alpha subunits is cell specific. Thus, G(olf) alpha is detected in normal rodent B cells and immortalized pancreatic B cell lines, whereas Gs alpha is more ubiquitously expressed. The cellular density of AC isoforms labeling (I, II, III, IV, V/VI) is also islet cell-specific and their distribution is age- and species-dependent. The identification of numerous signaling molecule subtypes, together with the discovery of their specific subcellular distribution, will help the functional characterization of their intraregulatory pathways, leading to the extrusion of insulin or glucagon secretory granules, and those leading to differentiation and apoptosis of islet cells.

Activation of adenylyl cyclases, regulation of insulin status, and cell survival by Gαolf in pancreatic β-cells

“…In addition, upstream signals emitted by the activated serpentine receptors can also greatly affect the relative efficiencies of G␣olf and G␣s in interacting with and stimulating differentially the eight membrane-bound AC isoforms. These enzymes are key elements in the transmission of signals from various insulin secretagogues such as tGLP-1 and GIP, which are known to induce cAMP production, insulin biosynthesis, and secretion (13). Similar to AC-III, sAC was not affected here by G␣olf, whereas the divalent cation Mn 2ϩ enhanced sAC-mediated cAMP generation, as previously described (8).…”

“…Alterations in G protein-coupled receptor signaling constitute the potential targets for pancreatic ␤-cell desensitization in diabetes (13,38). In ␤-cells, the glucose-dependent insulinotropic polypeptide (GIP) and its structurally related peptides, truncated glucagonlike polypeptide 1 (tGLP-1) and pituitary adenylyl cyclase (AC)-activating polypeptide, are critical activators of the cAMP pathway and potentiate glucoseinduced insulin release, insulin gene transcription, and ␤-cell growth (13).…”

Sulfonylurea Receptor Knockout Causes Glucose Intolerance in Mice That is Not Alleviated by Concomitant Somatostatin Subtype Receptor 5 Knockout

“…11,24 The alpha subtypes of G proteins have been shown to be islet cell-specific, and their distribution is age-and species-dependent. 25 SSTRs have been shown to decrease the intracellular calcium concentration and to directly affect the voltage-gated channels to prevent Ca 2ϩ influx. 26 SSTRs have also been linked to protein kinases and phosphatases, which act to regulate various downstream enzymes.…”

Pharmacological Agents That Directly Modulate Insulin Secretion

“…The possibility of the existence of more than one of the isomeric forms for the G-proteins (Emami et al, 1998), AC (Fimia and Sassone-Corsi, 2001), AKAPs, and PKA subunits in the ␤-cell, together with the compartmentalization of PKA with phosphatases (Coghlan et al, 1995) allows for multiple and differential levels of control of insulin secretion by glucose, hormones, and various drugs.…”