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

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-cl riven path, mode I-closed -> mode IIopen, and depolarization-induced deactivation (from mode I-open and/or from mode IIopen). How might this affect 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.