Molecular properties of voltage-gated K+ channels

Abstract

Subfamilies of voltage-activated K⁺ channels (Kv1-4) contribute to controlling neuron excitability and the underlying functional parameters. Genes encoding the multiple α subunits from each of these protein groups have been cloned, expressed and the resultant distinct K⁺ currents characterized. The predicted amino acid sequences showed that each α subunit contains six putative membrane-spanning α-helical segments (S1-6), with one (S4) being deemed responsible for the channels' voltage sensing. Additionally, there is an H5 region, of incompletely defined structure, that traverses the membrane and forms the ion pore; residues therein responsible for K⁺ selectivity have been identified. Susceptibility of certain K⁺ currents produced by the Shaker-related subfamily (Kv1) to inhibition by α-dendrotoxin has allowed purification of authentic K⁺ channels from mammalian brain. These are large (M_r ∼ 400 kD), octomeric sialoglycoproteins composed of α and Β subunits in a stoichiometry of (α)₄(Β)₄, with subtypes being created by combinations of subunit isoforms. Subsequent cloning of the genes for Β₁, Β₂ and Β₃ subunits revealed novel sequences for these hydrophilic proteins that are postulated to be associated with the α subunits on the inner side of the membrane. Coexpression of Β₁ and Kv1.4 subunits demonstrated that this auxiliary Β protein accelerates the inactivation of the K⁺ current, a striking effect mediated by an N-terminal moiety. Models are presented that indicate the functional domains pinpointed in the channel proteins.