Localization and Targeting of Voltage-Dependent Ion Channels in Mammalian Central Neurons

Abstract

The intrinsic electrical properties and the synaptic input-output relationships of neurons are governed by the action of voltage-dependent ion channels. The localization of specific population of ion channels with distinct functional properties at discrete sites in neurons dramatically impacts excitability and synaptic transmission. Molecular cloning studies have revealed a large family of genes encoding voltage-dependent ion channel principal and auxiliary subunits, most of which are expressed in mammalian central neurons. Much recent effort has focused on determining which of these subunits co-assemble into native neuronal channel complexes, and the cellular and subcellular distributions of these complexes, as a crucial step in understanding the contribution of these channels to specific aspects of neuronal function. Here we review progress made on recent studies aimed at determining the cellular and subcellular distribution of specific ion channel subunits in mammalian brain neurons using in situ hybridization, and immunohistochemistry. We also discuss the repertoire of ion channel subunits in specific neuronal compartments and implications for neuronal physiology. Finally, we discuss the emerging mechanisms for determining the discrete subcellular distributions observed for many neuronal ion channels. I. OVERVIEW OF MAMMALIAN BRAIN VOLTAGE-DEPENDENT ION CHANNELS A. IntroductionMammalian central neurons express a large repertoire of voltage-dependent ion channels (VDICs) that form selective pores in the neuronal membrane and confer diverse properties of intrinsic neuronal excitability. This allows mammalian neurons to display a richness of firing behaviors over a wide range of stimuli and firing frequencies. The complex electrical behavior of mammalian neurons is due to a huge array of VDICs with distinct ion flux rates and selectivity, although the major VDICs underlying neuronal excitability and electrical signaling are those selective for Na + , K + and Ca 2+ ions. Neuronal VDICs also exhibit widely differing properties of how sensitive their gating, or the opening or closing of the channels pore, is to changes in membrane potential. Different VDICs also differ in the kinetics of these gating events. Importantly in the terms of mammalian brain, different VDICs differ widely in their cellular expression and subcellular localization, impacting their relative contribution to brain

Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca 2+ influx, not Ca 2+ -exocytosis coupling

“…Hippocampal glutamate and GABA containing SVs differ in their release properties during AP trains as well as in their adaptive response to strong depolarization (29)(30)(31). Different profiles of presynaptic ion channel expression underlie exocytosis in glutamatergic and GABAergic synapses (32)(33)(34). Our findings that greater isoflurane sensitivity of glutamatergic compared with GABAergic SV exocytosis is determined by larger effects on Ca 2+ influx are consistent with transmitter phenotype-specific differences in expression of the presynaptic ion channels that determine [Ca 2+ ] i , including distinct subtypes of Na v , Ca v , and K v channels (35).…”

Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels

“…These findings imply that relative energy costs of fundamental features of cortical communication (e.g., action potentials, pre-and postsynaptic potentials, glial neurotransmitter and K + clearance, etc.) as well as physiological mechanisms for supplying mitochondrial energy for neuropil operations (e.g., hemoglobin, voltage-gated ion channels, glutamate and GABA receptors, and glucose and oxygen transport) are well-preserved through evolution (17,28,29,(44)(45)(46)(47)(48)(49). A constant interspecies ATP demand of cortical activity emphasizes the relevance of animal testing in experimental neuroscience studies.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…[48][49][50] All b-subunits and Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 are expressed in the brain. 51 Mutations in both a-or b-subunits have been associated, among other disorders, with epilepsy. 52 46,55 Five years later, BACE1 cleavage sites were mapped in the b2 subunit, which plays an important role in hippocampus and cortex.…”