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CO2/HCO3-responsive soluble adenylyl cyclase as a putative metabolic sensor

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Abstract

Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified a novel mammalian source of cAMP – soluble adenylyl cyclase (sAC) – that is regulated directly by bicarbonate ions (HCO3). As the concentration of HCO3 reflects cellular levels of carbon dioxide (CO2), energy-generating metabolic processes (which increase intracellular CO2) are poised to activate bicarbonate-responsive sAC. This direct link between metabolic activity, sAC and cAMP could represent an evolutionarily conserved mechanism of metabolic feedback regulation.

Section snippets

sAC as a metabolic pH sensor

Most catabolic processes converge on the citric acid cycle and on the electron transport chain, the end products of which are CO2 and ATP. In solutions with increasing partial pressures of CO2, water and CO2 are converted to HCO3 and H+, and vice versa (Fig. 4a). Unaided, this reaction reaches equilibrium in minutes, but in the presence of the ubiquitously expressed carbonic anhydrases (CA), it occurs almost instantaneously 24. CAs are represented in mammals by a large family whose members

Cyanobacteria

sAC is closely related to cyanobacterial adenylyl cyclases (ACs) 2, and HCO3 regulation is conserved across this vast evolutionary distance 9. Cyanobacteria are thought to be responsible for the photosynthesis that transformed the early pre-Cambrian atmosphere from one rich in CO2 to one rich in O2 (Ref. 35). In cyanobacteria, cAMP levels change in response to environmental conditions such as nutritional availability, and because they are photosynthetic, nutrients consist of CO2 and light (

Summary

sAC defines a novel cAMP signaling pathway with the potential to respond to pH, intracellular metabolism and ionic flux. As CO2/HCO3 is the main buffering system in the cell, levels of HCO3 would present an excellent signal for cellular homeostasis, and a direct link between CO2/ HCO3 levels and metabolism has been suggested 17, 18, 19, 20. In metabolism, pHi and/or cAMP effector proteins regulate key enzymes by direct modification or alterations in gene transcription. Therefore,

Acknowledgements

We would like to thank Geoffrey Pitt and Walter Boron, and also the members of the Levin/Buck laboratory for comments on the manuscript. Work in the authors’ laboratory is supported by NIH grants HD38722 (LRL), GM62328 (JB) and HD42060 (JB), and by the Irma T. Hirschl Trust (JB).

References (53)

  • S. van Es

    Adenylyl cyclase G, an osmosensor controlling germination of Dictyostelium spores

    J. Biol. Chem.

    (1996)
  • G.S. Pitt

    Structurally distinct and stage-specific adenylyl cyclase genes play different roles in Dictyostelium development

    Cell

    (1992)
  • D.L. Garbers

    A requirement of bicarbonate for Ca2+-induced elevations of cyclic AMP in guinea pig spermatozoa

    J. Biol. Chem.

    (1982)
  • G.A. Robison

    Cyclic AMP

    Annu. Rev. Biochem.

    (1968)
  • J. Buck

    Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • J. Buck

    Purification of soluble adenylyl cyclase

  • Jaiswal, B.S. and Conti, M. Identification and functional analysis of splice variants of the germ cell soluble adenylyl...
  • T. Braun et al.

    Development of a Mn2+-sensitive, ‘soluble’ adenylate cyclase in rat testis

    Proc. Natl. Acad. Sci. U. S. A.

    (1975)
  • T.C. Rich

    Cyclic nucleotide-gated channels colocalize with adenylyl cyclase in regions of restricted cAMP diffusion

    J. Gen. Physiol.

    (2000)
  • K.L. Dodge

    mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module

    EMBO J.

    (2001)
  • Y. Chen

    Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor

    Science

    (2000)
  • M.L. Sinclair

    Specific expression of soluble adenylyl cyclase in male germ cells

    Mol. Reprod. Dev.

    (2000)
  • J.O. Gordeladze

    Cellular localization of the Mn2+-dependent adenylyl cyclase (AC) in rat testis

    Int. J. Androl.

    (1981)
  • J.O. Gordeladze

    Cellular localization of the Mn2+-dependent adenylyl cyclase in the human testis

    Arch. Androl.

    (1982)
  • D.L. Garbers

    Regulation of spermatozoan cyclic nucleotide metabolism by egg factors

    Adv. Cyclic Nucleotide Res.

    (1978)
  • D.L. Garbers et al.

    The regulation of spermatozoa by calcium and cyclic nucleotides

    Adv. Cyclic Nucleotide Res.

    (1980)
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