CO2/HCO3(-)- and Calcium-regulated Soluble Adenylyl Cyclase As a Physiological ATP Sensor

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Oct 9

PMID 24100033

Citations 64

Authors

Jonathan H Zippin

Yanqiu Chen

Susanne G Straub

Kenneth C Hess

Ana Diaz

Dana Lee

Patrick Tso

George G Holz

Geoffrey W G Sharp

Lonny R Levin

Jochen Buck

Affiliations

Soon will be listed here.

Abstract

The second messenger molecule cAMP is integral for many physiological processes. In mammalian cells, cAMP can be generated from hormone- and G protein-regulated transmembrane adenylyl cyclases or via the widely expressed and structurally and biochemically distinct enzyme soluble adenylyl cyclase (sAC). sAC activity is uniquely stimulated by bicarbonate ions, and in cells, sAC functions as a physiological carbon dioxide, bicarbonate, and pH sensor. sAC activity is also stimulated by calcium, and its affinity for its substrate ATP suggests that it may be sensitive to physiologically relevant fluctuations in intracellular ATP. We demonstrate here that sAC can function as a cellular ATP sensor. In cells, sAC-generated cAMP reflects alterations in intracellular ATP that do not affect transmembrane AC-generated cAMP. In β cells of the pancreas, glucose metabolism generates ATP, which corresponds to an increase in cAMP, and we show here that sAC is responsible for an ATP-dependent cAMP increase. Glucose metabolism also elicits insulin secretion, and we further show that sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo.

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