Dual stretch responses of mHCN2 pacemaker channels: Accelerated activation, accelerated deactivation

Abstract

Mechanoelectric feedback in heart and smooth muscle is thought to depend on diverse channels that afford myocytes a mechanosensitive cation conductance. Voltage-gated channels (e.g., Kv1) are stretch sensitive, but the only voltage-gated channels that are cation permeant, the pacemaker or HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, have not been tested. To assess if HCN channels could contribute to a mechanosensitive cation conductance, we recorded IHCN in cell-attached oocyte patches before, during, and after stretch for a range of voltage protocols. ImHCN2 has voltage-dependent and instantaneous components; only the former wasstretch sensitive. Stretch reversibly accelerated hyperpolarization-induced I mHCN2 activation (likewise for IspHCN) and depolarization-induced deactivation. HCN channels (like Kv1 channels) undergo mode-switch transitions that render their activation midpoints voltage history dependent. The result, as seen from sawtooth clamp, is a pronounced hysteresis. During sawtooth clamp, stretch increased current magnitudes and altered the hysteresis pattern consistent with stretch-accelerated activation and deactivation. ImHCN2 responses to step protocols indicated that at least two transitions were mechanosensitive: an unspecified rate-limiting transition along the hyperpolarization-driven path, mode I closed→mode IIopen, and depolarization-induced deactivation (from mode Iopen and/or from mode IIopen). How might this affect cardiac rhythmicity? Since hysteresis patterns and "on" and off" IHCN responses all changed with stretch, predictions are difficult. For an empirical overview, we therefore clamped patches to cyclic action potential waveforms. During the diastolic potential of sinoatrial node cell and Purkinje fiber waveforms, net stretch effects were frequency dependent. Stretch-inhibited (SI) ImHCN2 dominated at low frequencies and stretch-augmented (SA) ImHCN2 was progressively more important as frequency increased. HCN channels might therefore contribute to either SI or SA cation conductances that in turn contribute to stretch arrhythmias and other mechanoelectric feedback phenomena. © 2007 by the Biophysical Society.