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

¹ Ottawa Health Research Inst

^* To whom correspondence should be addressed. E-mail: cmorris{at}ohri.ca.

Submitted on July 19, 2006
Revised on August 15, 2006
Accepted on 7 November 2006

	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 I_HCN in cell-attached oocyte patches before, during and after stretch, for a range of voltage protocols. I_mHCN2 has voltage-dependent and instantaneous components; only the former was stretch-sensitive. Stretch reversibly accelerated hyperpolarization-induced I_mHCN2 activation (likewise for I_spHCN) 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. I_mHCN2 responses to step-protocols indicated that at least two transitions were mechanosensitive: an unspecified rate-limiting transition along the hyperpolarization-driven path, Mode I_closedMode II_open, and depolarization-induced deactivation (from Mode I_open and/or from Mode II_open). How might this impact cardiac rhythmicity? Since hysteresis patterns and "on" and "off" I_HCN 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) I_mHCN2 dominated at low frequencies and stretch-augmented (SA) I_mHCN2 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.

Key Words: bilayer, channels, mechanosensitive, pacemaker, stretch, voltage-gated

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