Molecular diversity of vascular potassium channel isoforms

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 α-subunit and an ancillary β-subunit. The maxi-K and Kv channel α-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 α-subunit isoforms and β-subunit association occurs in a tissue-specific manner, thereby providing functional specificity. 3. The maxi-K channel α-subunit derives its molecular diversity by alternative splicing of a single-gene transcript to yield multiple isoforms that differ in their sensitivity to intra-cellular 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 β-subunits. Multiple β-subunits have been identified that can arise either from separate genes or alternative splicing of a α-subunit gene. The maxi-K channel α-subunits modulate the channel's Ca²⁺ and voltage sensitivity and kinetic and pharmacological properties. 4. The Kv channel α-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 hetero-tetramer, which can significantly change the Kv current phenotype in a given cell type. Association with a number of the ancillary β-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.