Molecular Dissection of IA in Cortical Pyramidal Neurons Reveals Three Distinct Components Encoded by Kv4.2, Kv4.3, and Kv1.4 α-Subunits

The rapidly activating and inactivating voltage-gated K+ (Kv) current, I-A, is broadly expressed in neurons and is a key regulator of action potential repolarization, repetitive firing, backpropagation (into dendrites) of action potentials, and responses to synaptic inputs. Interestingly, results from previous studies on a number of neuronal cell types, including hippocampal, cortical, and spinal neurons, suggest that macroscopic I-A is composed of multiple components and that each component is likely encoded by distinct Kv channel alpha-subunits. The goals of the experiments presented here were to test this hypothesis and to determine the molecular identities of the Kv channel alpha-subunits that generate I-A in cortical pyramidal neurons. Combining genetic disruption of individual Kv alpha-subunit genes with pharmacological approaches to block Kv currents selectively, the experiments here revealed that Kv1.4, Kv4.2, and Kv4.3 alpha-subunits encode distinct components of I-A that together underlie the macroscopic I-A in mouse (male and female) cortical pyramidal neurons. Recordings from neurons lacking both Kv4.2 and Kv4.3 (Kv4.2(-/-)/Kv4.3(-/-)) revealed that, although Kv1.4 encodes a minor component of I-A, the Kv1.4-encoded current was found in all the Kv4.2(-/-)/Kv4.3(-/-) cortical pyramidal neurons examined. Of the cortical pyramidal neurons lacking both Kv4.2 and Kv1.4, 90% expressed a Kv4.3-encoded I-A larger in amplitude than the Kv1.4-encoded component. The experimental findings also demonstrate that the targeted deletion of the individual Kv alpha-subunits encoding components of I-A results in electrical remodeling that is Kv alpha-subunit specific.