Voltage-gated Ca(2+) channels mediate Ca(2+) entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca(2+) currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca(2+) channels that have been characterized biochemically are complexes of a pore-forming alpha1 subunit of approximately 190-250 kDa; a transmembrane, disulfide-linked complex of alpha2 and delta subunits; an intracellular beta subunit; and in some cases a transmembrane gamma subunit. Ten alpha1 subunits, four alpha2delta complexes, four beta subunits, and two gamma subunits are known. The Cav1 family of alpha1 subunits conduct L-type Ca(2+) currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Cav2 family of alpha1 subunits conduct N-type, P/Q-type, and R-type Ca(2+) currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Cav3 family of alpha1 subunits conduct T-type Ca(2+) currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca(2+) current types. The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca(2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca(2+) entry by second messenger pathways and interacting proteins.

Structure and regulation of voltage-gated Ca2+ channels.

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/411.full.pdf

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

The human ATP-binding cassette (ABC) transporter superfamily

The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. Genetic variation in these genes is the cause of or contributor to a wide variety of human disorders with Mendelian and complex inheritance, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Conservation of the ATP-binding domains of these genes has allowed the identification of new members of the superfamily based on nucleotide and protein sequence homology. Phylogenetic analysis is used to divide all 48 known ABC transporters into seven distinct subfamilies of proteins. For each gene, the precise map location on human chromosomes, expression data, and localization within the superfamily has been determined. These data allow predictions to be made as to potential functions or disease phenotypes associated with each protein. In this paper, we review the current state of knowledge on all human ABC genes in inherited disease and drug resistance. In addition, the availability of the complete Drosophila genome sequence allows the comparison of the known human ABC genes with those in the fly genome. The combined data enable an evolutionary analysis of the superfamily. Complete characterization of all ABC from the human genome and from model organisms will lead to important insights into the physiology and the molecular basis of many human disorders.

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through L...

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Laboratory acquired infection with recombinant vaccinia virus containing an immunomodulating construct.

L-type Ca2+ channels of the embryonic mouse heart.

We investigated the dihydropyridine (DHP) inhibition of barium current (IBa) through the smooth muscle α1Cb and cardiac α1Ca splice variants of the L-type calcium channel using a whole-cell patch-clamp method. IC50 values for inhibition of current amplitude of the α1Cb channel were three to fivefold lower than for the α1Ca channel at holding potentials between –80 mV and –30 mV. No difference was found in either the transition of the channels into an inactivated state in the absence or presence of drug, or in the recovery from inactivation under control conditions. However, isradipine slowed the recovery from inactivation of α1Ca more effectively than α1Cb. To evaluate the interaction of isradipine with the open channel state of both splice variants, interactions with the inactivated state were selectively suppressed by the mutation of three amino acids in the IVS6 segment (Y1485I, M1486F, I1493L) in α1CbCh30 and α1CaCh30 channels. The extent of this interaction was seen by an acceleration of current decay. This was found to be identical for both splice variants. Our results suggest that the higher DHP selectivity of the α1Cb versus the α1Ca channel is caused by the structural difference in the binding site and not by different transitions between resting, open and inactivated states.

Norbert Klugbauer

Papers

Laboratory acquired infection with recombinant vaccinia virus containing an immunomodulating construct.

L-type Ca2+ channels of the embryonic mouse heart.

State- and isoform-dependent interaction of isradipine with the α1C L-type calcium channel

Gating of the expressed Cav3.1 calcium channel

Chapter 17 – Molecular Biology and Expression of Smooth Muscle L-Type Calcium Channels