Mechanosensitive Gating of Kv Channels

Abstract

K-selective voltage-gated channels (Kv) are multi-conformation bilayer-embedded proteins whose mechanosensitive (MS) Popen(V) implies that at least one conformational transition requires the restructuring of the channel-bilayer interface. Unlike Morris and colleagues, who attributed MS-Kv responses to a cooperative V-dependent closed-closed expansion↔compaction transition near the open state, Mackinnon and colleagues invoke expansion during a V-independent closed↔open transition. With increasing membrane tension, they suggest, the closed↔open equilibrium constant, L, can increase >100-fold, thereby taking steady-state Popen from 0→1; “exquisite sensitivity to small…mechanical perturbations”, they state, makes a Kv “as much a mechanosensitive…as…a voltage-dependent channel”. Devised to explain successive g K (V) curves in excised patches where tension spontaneously increased until lysis, their L-based model falters in part because of an overlooked IK feature; with recovery from slow inactivation factored in, their g(V) datasets are fully explained by the earlier model (a MS V-dependent closed-closed transition, invariant L≥4). An L-based MS-Kv predicts neither known Kv time courses nor the distinctive MS responses of Kv-ILT. It predicts Kv densities (hence gating charge per V-sensor) several-fold different from established values. If opening depended on elevated tension (L-based model), standard g K (V) operation would be compromised by animal cells’ membrane flaccidity. A MS V-dependent transition is, by contrast, unproblematic on all counts. Since these issues bear directly on recent findings that mechanically-modulated Kv channels subtly tune pain-related excitability in peripheral mechanoreceptor neurons we undertook excitability modeling (evoked action potentials). Kvs with MS V-dependent closed-closed transitions produce nuanced mechanically-modulated excitability whereas an L-based MS-Kv yields extreme, possibly excessive (physiologically-speaking) inhibition.

The Hv1 proton channel responds to mechanical stimuli

“…Voltage-gated potassium and sodium channels are known to be sensitive to mechanical stimulation, as their activation by membrane depolarization is modulated by membrane stretch (Laitko et al, 2006;Beyder et al, 2010;Schmidt et al, 2012;Hao et al, 2013). However, whether the effect of membrane stretch is mediated by their four VSDs or their pore domain is a subject of debate (Tabarean and Morris, 2002;Schmidt et al, 2012;Morris et al, 2015). Because the Hv1 channel lacks the pore domain and has a dimeric, rather than tetrameric, structural organization, it represents a simpler model to study how mechanical forces affect VSDs.…”

“…Hv1 mechanosensitivity thus provides a mechanistic link between channel activation in microglia and brain damage after stroke. Beyder et al, 2010;Schmidt et al, 2012;Morris et al, 2015), we investigated the response of Hv1 to this particular type of mechanical stimulus. We found that membrane stretch strongly affects Hv1 gating and that the channel's activation rate is the most mechanosensitive parameter.…”

Ion current and action potential alterations in peripheral neurons subject to uniaxial strain

“…The effect of stretch on ion channel populations has been principally investigated using localized membrane suction as a method for cell membrane deformation (Beyder et al, ; Morris & Juranka, ; Morris, Prikryl, & Joós, ; Wang et al, ). Although this allows simultaneous deformation and ion current recording, it does not closely replicate strains occurring in nerves in vivo, where the whole cell is subject to deformation.…”

Simulations of Myenteric Neuron Dynamics in Response to Mechanical Stretch

“…Studies in other sensory systems suggested the mechanoreceptors convert mechanical stimuli to receptor potentials via activation of ionic channels. The opening of the mechanosensitive channel is selective to sodium or potassium ions and the channel activation was voltage-dependent [ 17 , 27 , 28 ]. However, studies on the mechanosensitive channel of putative aortic baroreceptor neurons found that the channel currents appeared to be linear to the voltage and the channel opening frequency increased with pressure.…”