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Carbonic Anhydrases and Brain pH in the Control of Neuronal Excitability

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Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

Part of the book series: Subcellular Biochemistry ((SCBI,volume 75))

Abstract

H+ ions are remarkably efficient modulators of neuronal excitability. This renders brain functions highly sensitive to small changes in pH which are generated “extrinsically” via mechanisms that regulate the acid–base status of the whole organism; and “intrinsically”, by activity-induced transmembrane fluxes and de novo generation of acid–base equivalents. The effects of pH changes on neuronal excitability are mediated by diverse, largely synergistically-acting mechanisms operating at the level of voltage- and ligand-gated ion channels and gap junctions. In general, alkaline shifts induce an increase in excitability which is often intense enough to trigger epileptiform activity, while acidosis has the opposite effect. Brain pH changes show a wide variability in their spatiotemporal properties, ranging from long-lasting global shifts to fast and highly localized transients that take place in subcellular microdomains. Thirteen catalytically-active mammalian carbonic anhydrase isoforms have been identified, whereof 11 are expressed in the brain. Distinct CA isoforms which have their catalytic sites within brain cells and the interstitial fluid exert a remarkably strong influence on the dynamics of pH shifts and, consequently, on neuronal functions. In this review, we will discuss the various roles of H+ as an intra- and extracellular signaling factor in the brain, focusing on the effects mediated by CAs. Special attention is paid on the developmental expression patterns and actions of the neuronal isoform, CA VII. Studies on the various functions of CAs will shed light on fundamental mechanisms underlying neuronal development, signaling and plasticity; on pathophysiological mechanisms associated with epilepsy and related diseases; and on the modes of action of CA inhibitors used as CNS-targeting drugs.

Susan C. Frost and Robert McKenna (eds.). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications

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Acknowledgments

The authors’ original research work has been supported by the Academy of Finland, the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, and the Letten Foundation. We thank Prof. Juha Voipio for discussions and constructive comments on the manuscript.

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Authors and Affiliations

  1. Department of Biosciences, University of Helsinki, Helsinki, Finland

    Eva Ruusuvuori

  2. Department of Biosciences and Neuroscience Center, University of Helsinki, Helsinki, Finland

    Kai Kaila

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  1. Eva Ruusuvuori
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  2. Kai Kaila
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Correspondence to Kai Kaila .

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  1. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Susan C. Frost

  2. Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA

    Robert McKenna

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Ruusuvuori, E., Kaila, K. (2014). Carbonic Anhydrases and Brain pH in the Control of Neuronal Excitability. In: Frost, S., McKenna, R. (eds) Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry, vol 75. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7359-2_14

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