Go2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells.
The neuropeptide galanin regulates numerous physiological activities in the body, including feeding and metabolism, learning and memory, nociception and spinal reflexes, and anxiety and related behaviors. Modulation of blood glucose levels by suppressing insulin release was the first reported activity for galanin. This inhibition was mediated by one or more pertussis toxin-sensitive G proteins of the G(i/o) subfamily. However, the molecular identities of the specific G protein(s) and intracellular effectors have not been fully revealed. Recently, we demonstrated that mice lacking G(o)2, but not other members of the G(i/o) protein family, secrete more insulin than controls upon glucose challenge, indicating that G(o)2 is a major transducer for the inhibitory regulation of insulin secretion. In this study, we investigated galanin signaling mechanisms in β cells using cell biological and electrophysiological approaches. We found that islets lacking G(o)2, but not other G(i/o) proteins, lose the inhibitory effect of galanin on insulin release. Potentiation of ATP-sensitive potassium (K(ATP)) and inhibition of calcium currents by galanin were disrupted by anti-G(o)2α antibodies. Galanin actions on K(ATP) and calcium currents were completely lost in G(o)2(-/-) β cells. Furthermore, the hyperglycemic effect of galanin is also blunted in G(o)2(-/-) mice. Our results demonstrate that G(o)2 mediates the inhibition of insulin release by galanin by regulating both K(ATP) and Ca(2+) channels in mice. Our findings provide insight into galanin's action in glucose homeostasis. The results may also be relevant to the understanding of galanin signaling in other biological systems, especially the central nervous system.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Guanghua
G
Tang
Ying
Y
Wang
Sangeun
S
Park
Neil S
NS
Bajpayee
Diana
D
Vi
Yoshiko
Y
Nagaoka
Lutz
L
Birnbaumer
Meisheng
M
Jiang
D000818:Animals; D019204:GTP-Binding Proteins / Q000502:physiology*; D019004:Galanin / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D044088:Receptors, Galanin / Q000502:physiology; D015398:Signal Transduction
D007328:Insulin; D044088:Receptors, Galanin; D019004:Galanin; D019204:GTP-Binding Proteins