Elsevier

Neuroscience Letters

Volume 486, Issue 2, 10 December 2010, Pages 107-116
Neuroscience Letters

Review
Signaling complexes of voltage-gated sodium and calcium channels

https://doi.org/10.1016/j.neulet.2010.08.085Get rights and content

Abstract

Membrane depolarization and intracellular Ca2+ transients generated by activation of voltage-gated Na+ and Ca2+ channels are local signals, which initiate physiological processes such as action potential conduction, synaptic transmission, and excitation–contraction coupling. Targeting of effector proteins and regulatory proteins to ion channels is an important mechanism to ensure speed, specificity, and precise regulation of signaling events in response to local stimuli. This article reviews experimental results showing that Na+ and Ca2+ channels form local signaling complexes, in which effector proteins, anchoring proteins, and regulatory proteins interact directly with ion channels. The intracellular domains of these channels serve as signaling platforms, mediating their participation in intracellular signaling processes. These protein–protein interactions are important for regulation of cellular plasticity through modulation of Na+ channel function in brain neurons, for short-term synaptic plasticity through modulation of presynaptic CaV2 channels, and for the fight-or-flight response through regulation of postsynaptic CaV1 channels in skeletal and cardiac muscle. These localized signaling complexes are essential for normal function and regulation of electrical excitability, synaptic transmission, and excitation–contraction coupling.

Research highlights

▶ Depolarization and Ca2+ transients generated by Na+ and Ca2+ channels are local signals. ▶ Targeting of effectors and regulatory proteins ensures signaling specificity and speed. ▶ Na+ and Ca2+ channels form signaling complexes with effectors and regulatory proteins. ▶ The intracellular domains of Na+ and Ca2+ channels serve as signaling platforms. ▶ Localized signaling complexes are essential for normal function and regulation.

Introduction

The electrical signals produced by ion channels and the resulting Ca2+ entry that initiates intracellular responses are local signaling events. Modulation of ion channels is a dynamic process that is precisely controlled in space and time [12], [18]. Targeting and localization of signaling enzymes to discrete subcellular compartments or substrates is an important regulatory mechanism ensuring specificity of signaling events in response to local stimuli [89]. This article describes signaling complexes formed by three representative ion channels: brain Na+ channels (NaV1.2) that initiate and conduct action potentials, presynaptic Ca2+ channels (CaV2.1) that conduct P/Q-type Ca2+ currents and initiate synaptic transmission, and muscle Ca2+ channels (CaV1.1 and CaV1.2) that initiate excitation–contraction coupling. In each case, signaling proteins and anchoring proteins that regulate these channels or are effectors in downstream signaling pathways bind to specific sites on their intracellular domains, and these protein–protein interactions are required for normal signal transduction in nerve and muscle cells.

Section snippets

Experimental approaches for analysis of ion channel signaling complexes

Biochemical, proteomic, and functional approaches have been combined in the analysis of ion channel signaling complexes. The biochemical approach usually begins with purification of an ion channel and identification of associated subunits and other interacting proteins. The initial signaling complexes of voltage-gated sodium and calcium channels were defined in this way as described below. Proteomic methods offer a broader view of ion channel signaling complexes by defining all of their

A signaling complex of brain Na+ channels mediates cellular plasticity

Neuromodulation of electrical excitability is a fundamental mechanism in many aspects of learning, memory, and physiological regulation. Voltage-gated Na+ channels are responsible for the initiation and propagation of action potentials [52]. Their regulation by neurotransmitters and second messengers provides an important form of cellular plasticity, which controls the excitability of central neurons in response to the sum of their synaptic inputs, sets the threshold for excitability, and

A presynaptic Ca2+ channel signaling complex mediates short-term synaptic plasticity

Presynaptic CaV2 channels conduct P/Q-, N-, and R-type Ca2+ currents, which initiate synaptic transmission. The efficiency of neurotransmitter release depends on the third or fourth power of entering Ca2+. This steep dependence of neurotransmission on Ca2+ entry makes the presynaptic Ca2+ channel an unusually sensitive target of regulation. CaV2.1 channels conducting P/Q-type Ca2+ currents are the predominant pathway for Ca2+ entry initiating fast release of classical neurotransmitters like

Muscle CaV1 channel signaling complexes regulate excitation–contraction coupling in the fight-or-flight response

Skeletal muscle CaV1 channels. Skeletal muscle CaV1.1 channels have been the primary experimental model for biochemical studies of Ca2+ channels [24], [36], [118]. Both the pore-forming α1 subunit and the auxiliary β subunit are phosphorylated by PKA [25], [35], [118]. The α1 subunit is truncated by proteolytic processing of the C-terminal domain [27], [28], and the primary sites of PKA phosphorylation are located in the distal C-terminus beyond the point of proteolytic cleavage [102], [103].

The effector checkpoint hypothesis for Ca2+ channel regulation

Three well-defined examples of Ca2+ channel regulation suggest the effector-checkpoint hypothesis for Ca2+ channel regulation [59]. Skeletal muscle CaV1.1 channels in transverse tubules interact directly with the ryanodine-sensitive Ca2+ release channels in the sarcoplasmic reticulum, which serve as their effectors in excitation–contraction coupling [85]. Deletion of the gene for the ryanodine-sensitive Ca2+ release channel dramatically reduces the activity of the CaV1.1 channels [82]. Thus,

Perspective

The idea that ion channels are multi-protein complexes stems from early biochemical studies showing that they are multi-subunit proteins and now is amplified by the extensive evidence for signaling complexes that are nucleated by ion channels. The work reviewed here shows that voltage-gated Na+ and Ca2+ channels form specific signaling complexes that are essential for their physiological functions and for their regulation. Electrical signals generated by Na+ and Ca2+ channels are inherently

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