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Direct activation of fission yeast adenylate cyclase by the Gpa2 Galpha of the glucose signaling pathway.

ABSTRACT: G protein-mediated signaling is implicated in yeast and fungal cAMP pathways. By two-hybrid screens and pull-down experiments, we show that the fission yeast Gpa2 Galpha binds an N-terminal domain of adenylate cyclase, comprising a moderately conserved sequence within a region otherwise poorly related to other fungal adenylate cyclases. Overexpressing this domain in yeast perturbs cAMP signaling, which is restored by Gpa2 coexpression. Mutations affecting this domain, over 1,100 residues from the catalytic domain, alter glucose-triggered cAMP signaling. This is evidence for direct activation of adenylate cyclase by a fungal G protein and suggests a distinct activation mechanism from that of mammals.

SUBMITTER: Ivey FD

PROVIDER: S-EPMC1087962 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Direct activation of fission yeast adenylate cyclase by the Gpa2 Galpha of the glucose signaling pathway.

Ivey F Douglas FD Hoffman Charles S CS

Proceedings of the National Academy of Sciences of the United States of America 20050414 17

G protein-mediated signaling is implicated in yeast and fungal cAMP pathways. By two-hybrid screens and pull-down experiments, we show that the fission yeast Gpa2 Galpha binds an N-terminal domain of adenylate cyclase, comprising a moderately conserved sequence within a region otherwise poorly related to other fungal adenylate cyclases. Overexpressing this domain in yeast perturbs cAMP signaling, which is restored by Gpa2 coexpression. Mutations affecting this domain, over 1,100 residues from th ...[more]

PMID: 15831585

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Project description:ObjectiveThe unraveling of the elaborate brain networks that control glucose metabolism presents one of the current challenges in diabetes research. Within the central nervous system, the hypothalamus is regarded as the key brain area to regulate energy homeostasis. The aim of the present study was to investigate the hypothalamic mechanism involved in the hyperglycemic effects of the neuropeptide pituitary adenylyl cyclase-activating polypeptide (PACAP).Research design and methodsEndogenous glucose production (EGP) was determined during intracerebroventricular infusions of PACAP-38, vasoactive intestinal peptide (VIP), or their receptor agonists. The specificity of their receptors was examined by coinfusions of receptor antagonists. The possible neuronal pathway involved was investigated by 1) local injections in hypothalamic nuclei, 2) retrograde neuronal tracing from the thoracic spinal cord to hypothalamic preautonomic neurons together with Fos immunoreactivity, and 3) specific hepatic sympathetic or parasympathetic denervation to block the autonomic neuronal input to liver.ResultsIntracerebroventricular infusion of PACAP-38 increased EGP to a similar extent as a VIP/PACAP-2 (VPAC2) receptor agonist, and intracerebroventricular administration of VIP had significantly less influence on EGP. The PACAP-38 induced increase of EGP was significantly suppressed by preinfusion of a VPAC2 but not a PAC1 receptor antagonist, as well as by hepatic sympathetic but not parasympathetic denervation. In the hypothalamus, Fos immunoreactivity induced by PACAP-38 was colocalized within autonomic neurons in paraventricular nuclei projecting to preganglionic sympathetic neurons in the spinal cord. Local infusion of PACAP-38 directly into the PVN induced a significant increase of EGP.ConclusionsThis study demonstrates that PACAP-38 signaling via sympathetic preautonomic neurons located in the paraventricular nucleus is an important component in the hypothalamic control of hepatic glucose production.

Dataset Information

Direct activation of fission yeast adenylate cyclase by the Gpa2 Galpha of the glucose signaling pathway.

Publications

Direct activation of fission yeast adenylate cyclase by the Gpa2 Galpha of the glucose signaling pathway.

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