Ruusuvuori Eva, Kaila Kai
Department of Biosciences, University of Helsinki, Helsinki, Finland,
Subcell Biochem. 2014;75:271-90. doi: 10.1007/978-94-007-7359-2_14.
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.
氢离子是神经元兴奋性的高效调节剂。这使得脑功能对pH值的微小变化高度敏感,pH值的变化可通过调节整个机体酸碱平衡状态的“外在”机制以及由活动诱导的跨膜通量和酸碱当量的从头生成的“内在”机制产生。pH值变化对神经元兴奋性的影响是由多种在电压门控离子通道、配体门控离子通道和缝隙连接水平协同作用的机制介导的。一般来说,碱性转变会导致兴奋性增加,这种增加通常强烈到足以引发癫痫样活动,而酸中毒则具有相反的效果。脑pH值变化在时空特性上表现出很大的变异性,范围从持久的全局变化到在亚细胞微区发生的快速且高度局部化的瞬变。已鉴定出13种具有催化活性的哺乳动物碳酸酐酶同工型,其中11种在脑中表达。在脑细胞和细胞间液中具有催化位点的不同碳酸酐酶同工型对pH值变化的动力学以及因此对神经元功能有显著影响。在这篇综述中,我们将讨论氢离子作为脑内和细胞外信号因子的各种作用,重点关注碳酸酐酶介导的效应。特别关注神经元同工型碳酸酐酶VII的发育表达模式和作用。对碳酸酐酶各种功能的研究将揭示神经元发育、信号传导和可塑性的基本机制;与癫痫及相关疾病相关的病理生理机制;以及用作中枢神经系统靶向药物的碳酸酐酶抑制剂的作用方式。