alexa Three-Dimensional Dynamic Structure of the Liquid-Ordered Domain in Lipid Membranes as Examined by Pulse-EPR Oxygen Probing


Journal of Clinical & Experimental Ophthalmology

Author(s): Subczynski WK, Wisniewska A, Hyde JS, Kusumi A

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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 was stretch sensitive. Stretch reversibly accelerated hyperpolarization-induced ImHCN2 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 Iclosed→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.

This article was published in Biophysical Journal and referenced in Journal of Clinical & Experimental Ophthalmology

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