Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion
channels and myelination. One recently appreciated example is the tight colocalization of Kv7 potassium channels and voltage-gated
sodium (Nav ) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these Kv7 channels and the
functional impact of colocalization with Nav channels remain poorly understood. Here, we quantitatively examined Kv7 channels in
myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording.Kv7.2 and 7.3
immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density
estimates, which increased from12 (proximal) to 150 pSm2 (distal). The axonal initial segment and nodal M-currents were similar
in voltage dependence and kinetics, carried by Kv7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly
activated with single-exponential time constants (15 ms at 28 mV). Experiments and computational modeling showed that while
somatodendritic Kv7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and
repetitive firing, axonal Kv7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains
Kv7.2/7.3 channels were found to increase Nav channel availability and action potential amplitude by stabilizing the resting membrane
potential. Thus, Kv7 clustering near axonal Nav channels serves specific and context-dependent roles, both restraining initiation and
enhancing conduction of the action potential.