Classification Structure and Distribution of VGCCs

Central to the operation of the Vm-dependent Ca2+ signaling pathway is the incorporation of VGCCs into the electrical membrane activity. These channels are large multisubunit proteins that span the plasma membrane to provide a Ca2+-selective pathway into the cytosol. At rest, the channel remains closed, blocking Ca2+ entry into the cell. In response to membrane depolarization, the molecular "gates" of the channel open and Ca2+ is free to flow through the aqueous pore of the channel. The voltage-dependent opening of ionic channels is called activation. The direction of Ca2+ flow through the channel pore is determined by the electrochemical gradient for Ca2+, which under normal conditions drives Ca2+ from the extracellular milieu into the cytosol. After only a few milliseconds, or in as much as several hundred milliseconds, the channel closes and the flow of Ca2+ is again blocked. The closing of an ionic channel is called inactivation. Following inactivation, the channel returns to its resting state until the next membrane depolarization triggers the whole process over again (see also the chapter by H. A. Fozzard and D. J. Nelson in this volume).

The Ca2+ selectivity and voltage sensitivity of these channels are common features among two major groups of VGCCs, which are separated by their sensitivity to changes in Vm. The first group of channels requires only weak membrane depolarization to open. Consequently, they are activated at relatively hyper-polarized membrane potentials and are known as low-voltage activated (LVA) Ca2+ channels. The most distinguishing feature of this group, however, is their rapid inactivation and requirement for strong membrane hyperpolarization to bring them out of steady-

Louvers Facade Diagram
Fig. 7. Structural relationship and functional characteristics among arsubunits of high-voltage-activated calcium channels. (Derived from Wheeler DB [Prog Brain Res 1995; 105:65] with permission.)

state inactivation. Owing to the rapid inactivation of these channels, they are often referred to as transient or T-type Ca2+ channels. The second group of VGCCs requires moderate to strong membrane depolarization to open. They are therefore activated at relatively depolarized membrane potentials and are known as high-voltage activated (HVA) Ca2+ channels. Compared to LVA channels, most HVA channels inactivate slowly, or exhibit little to no inactivation during sustained membrane depolarization. Among this group, biophysical and pharmacological studies have identified multiple subtypes that can be distinguished by their ion selectivity, single channel conductance, pharmacology, metabolic regulation, and tissue localization. Based on these criteria, five HVA Ca2+ channel subtypes have been identified to date: L-, N-, P, Q-, and R-type Ca2+ channels (Fig. 7).

Consistent with the functional studies, molecular cloning has identified several genes that encode different VGCC subtypes. The first Ca2+ channel was purified from skeletal muscle, as it is a highly enriched source of L-type Ca2+ channels. Purification of the channel identified five subunits, including a large a1-(200-260 kDa) subunit and four smaller ancillary subunits: a2, P, y, and 5. The a1-subunit consists of four homologous repeats, each one composed of six transmembrane segments (Fig. 8). Located within the a1-subunit are the voltage sensor, gating machinery, channel pore, and multiple protein kinase A and cAMP-dependent-kinase phosphorylation sites. Since the first a1-subunit was cloned from skeletal muscle, at least seven isoforms have been identified, including the a1S, a1C, a1D, a1B, a1A, a1E, and a1G. The a1S-, a1C-, and a1D-subunits make up the L-type Ca2+ channels in skeletal muscle, cardiac muscle, and neurons, respectively. The a1B subunit is associated with N-type channels in neurons. The a1A-subunitis associated with both P- and Q-type neuronal channels, and the a1E-subunit with the R-type channels (Fig. 7). Finally, the a1G-subunit has been linked to T-type Ca2+ channels. Mutations in the a1-subunit of VGCCs are the underlying defects in a growing number of human disorders, including hypokalemic periodic paralysis, hemiplegic migraine, episodic ataxia type

Hypokalaemic Periodic Paralysis Migraine

Fig. 8. Schematic representation of voltage-gated calcium channel complex. Diagram indicates the putative transmembrane topologies of the a1-subunit, as well as a2-, P-, and 8-subunits. The binding sites for the Gp/y dimer are also shown. (Derived from Dolphin AC [J Physiol 1998; 506:3] with permission.)

Fig. 8. Schematic representation of voltage-gated calcium channel complex. Diagram indicates the putative transmembrane topologies of the a1-subunit, as well as a2-, P-, and 8-subunits. The binding sites for the Gp/y dimer are also shown. (Derived from Dolphin AC [J Physiol 1998; 506:3] with permission.)

2, and cerebellar ataxia. Although the a1-subunit can function as a VGCC when expressed alone, the ancillary subunits have a substantial impact on current amplitude, voltage dependence, and activation/ inactivation kinetics. In addition, the p1-subunit is a target for second-messenger-mediated modulation of VGCCs.

Coexpression of several Ca2+ channel subtypes in a single cell is common in neurons and endocrine cells. For example, both T- and L-type Ca2+ channels are expressed in pituitary lactotrophs, gonadotrophs, corticotrophs, somatotrophs, and melanotrophs. In sensory neurons, T-type and L-type Ca2+ channels are coexpressed with N-type Ca2+ channels. In other neurons, P/Q-type Ca2+ channels are also found in conjunction with other VGCC subtypes. Although multiple Ca2+ channel subtypes may be coexpressed in the same cell, they are often distributed nonuni-formly in different regions. In inferior olivary neurons, HVA Ca2+ channels are found mostly, but not exclusively, in the dendrites, whereas LVA Ca2+ channels are found predominately in the cell body. The distribution of HVA Ca2+ channel subtypes within the same cell may also be nonuniform. In neurons, extensive expression of the a1B- and a1A-subunit of the N- and P/Q-type Ca2+ channels has been found in the dendritic shafts and presynaptic nerve terminals, but not the cell body. Conversely, the a1C- and a1D-subunit of L-type Ca2+ channels were found predominately in the soma and proximal dendrites. The a1E-subunit of the R-type Ca2+ channel was found predominantly in the cell body of central nervous system (CNS) neurons. The nonuniform distribution of Ca2+ channel subtypes likely reflects their different functional roles. For example, the slow inactivation kinetics of N- and P/Q-type Ca2+ channels make them ideal for prolonging AP duration, allowing enough Ca2+ entry to stimulate exocytosis in the presynaptic nerve terminals.

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