Molecular Diversity Of Vascular Potassium Channel Isoforms

Abstract

1. One essential role for potassium channels in vascular smooth muscle is to buffer cell excitation and counteract vasoconstrictive influences. Several molecular mechanisms regulate potassium channel function. The interaction of these mechanisms may be one method for fine-tuning potassium channel activity in response to various physiological and pathological challenges. 2. The most prevalent K+ channels in vascular smooth muscle are large-conductance calcium- and voltage-sensitive channels (maxi-K channels) and voltage-gated channels (Kv channels). Both channel types are complex molecular structures consisting of a pore-forming alpha-subunit and an ancillary beta-subunit. The maxi-K and Kv channel alpha-subunits assemble as tetramers and have S4 transmembrane domains that represent the putative voltage sensor. While most vascular smooth muscle cells identified to date contain both maxi-K and Kv channels, the expression of individual alpha-subunit isoforms and beta-subunit association occurs in a tissue-specific manner, thereby providing functional specificity. 3. The maxi-K channel alpha-subunit derives its molecular diversity by alternative splicing of a single-gene transcript to yield multiple isoforms that differ in their sensitivity to intracellular Ca2+ and voltage, cell surface expression and post- translational modification. The ability of this channel to assemble as a homo- or heterotetramer allows for fine-tuning control to intracellular regulators. Another level of diversity for this channel is in its association with accessory beta-subunits. Multiple beta-subunits have been identified that can arise either from separate genes or alternative splicing of a beta-subunit gene. The maxi-K channel beta-subunits modulate the channel's Ca2+ and voltage sensitivity and kinetic and pharmacological properties. 4. The Kv channel alpha-subunit derives its diverse nature by the expression of several genes. Similar to the maxi-K channel, this channel has been shown to assemble as a homo- and heterotetramer, which can significantly change the Kv current phenotype in a given cell type. Association with a number of the ancillary beta-subunits affects Kv channel function in several ways. Beta-subunits can induce inactivating properties and act as chaperones, thereby regulating channel cell-surface expression and current kinetics.

Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells

“…4). The K v channels consist of pore-forming ␣-subunits and ancillary ␤-subunits, similar to the BK Ca channels (33). Although many studies addressed the physiological and pharmacological properties of vascular K v channels, few examined the molecular subtypes of the K v channels.…”

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

“…Although this drug effectively reduced hypertension and ameliorated ischemic heart disease (14,16,17), it also inhibited L-type Ca 2+ channels via the production of an active metabolite through intracellular hydrolysis (18 (21,22). Among these, the K V channel plays a key role in regulating resting membrane potential and thereby maintaining basal vascular tone (21,23,24). In fact, the inhibition of K V channels produces membrane depolarization and vasoconstriction in some arteries.…”

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

“…Unfor-tunately, this drug was withdrawn from the market because it inhibited cytochrome P450 enzymes (antihistamines), leading to drug-drug interactions (6 -8 (9,10). Of these, Kv channels play a major role in the control of resting membrane potential, which contributes to maintain basal tone (9,11,12). Inhibition of Kv channels by Kv channel inhibitors induces depolarization and vasoconstriction in arteries (13 -15).…”