title: Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.
abstract: 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 K(v)7 potassium channels and voltage-gated sodium (Na(v)) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these K(v)7 channels and the functional impact of colocalization with Na(v) channels remain poorly understood. Here, we quantitatively examined K(v)7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. K(v)7.2 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 from ~12 (proximal) to 150 pS μm(-2) (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by K(v)7.2/7.3 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 K(v)7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal K(v)7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains K(v)7.2/7.3 channels were found to increase Na(v) channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, K(v)7 clustering near axonal Na(v) channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential.
authors.affiliation: Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences, 1105 BA, Amsterdam, The Netherlands, Baylor College of Medicine, Baylor Plaza, Houston, Texas 77030, Eccles Institute for Neuroscience, The Australian National University, Canberra 0200, Australian Capital Territory, Australia, and Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Arne
authors.initials: A
authors.lastname: Battefeld
authors.forename: Baouyen T
authors.initials: BT
authors.lastname: Tran
authors.forename: Jason
authors.initials: J
authors.lastname: Gavrilis
authors.forename: Edward C
authors.initials: EC
authors.lastname: Cooper
authors.forename: Maarten H P
authors.initials: MH
authors.lastname: Kole
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000502:physiology*; D051658:KCNQ2 Potassium Channel / Q000502:physiology*; D051659:KCNQ3 Potassium Channel / Q000502:physiology*; D008297:Male; D019579:Neocortex / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel
keywords: Kv7; axon; excitability