A role for G(z) in pancreatic islet beta-cell biology.
Glucose-stimulated insulin secretion and beta-cell growth are important facets of pancreatic islet beta-cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G(z) and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic beta-cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G alpha(z) impacts are intact in beta-cells, and G alpha(z) activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) beta-cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G alpha(i) family members are not involved in this process in this beta-cell line. Indeed, overexpression of a selective deactivator of G alpha(z), the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G alpha(z) expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) beta-cell line couples to G(z) predominantly and perhaps even exclusively. These data provide the first evidence for G(z) signaling in pancreatic beta-cells, and identify an endogenous receptor-mediated signaling process in beta-cells that is dependent on G alpha(z) function.
Kimple
Michelle E
ME
Department of Pharmacology and Cancer Biology, Duke University, Medical Center, Durham, North Carolina 27710, USA.
Nixon
Andrew B
AB
Kelly
Patrick
P
Bailey
Candice L
CL
Young
Kenneth H
KH
Fields
Timothy A
TA
Casey
Patrick J
PJ
D000818:Animals; D045744:Cell Line, Tumor; D044385:GTP-Binding Protein alpha Subunits / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D044385:GTP-Binding Protein alpha Subunits; C490963:Gnaz protein, rat; C545637:Ptger1 protein, rat; D043562:Receptors, G-Protein-Coupled; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D020827:rap1 GTP-Binding Proteins