Cardiac Mechano-Gated Ion Channels and Arrhythmias

Abstract

Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, are exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intra-cardially, and are thus maintained even in heart transplant recipients. Although mechano-sensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechano-transduction have started to emerge. Mechano-gated ion channels are cardiac mechano-receptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them. Cardiac electrophysiology is acutely affected by the heart’s mechanical environment. Mechano-electric feedback affects excitability, conduction, and electrical load, and remains an underestimated player in arrhythmogenesis. The utility of therapeutic interventions targeting acute mechano-electrical transduction is an open field worthy of further study.

Asymmetric mechanosensitivity in a eukaryotic ion channel

“…tension (23,24), and their mechanosensitivity is thought to be important for many diverse physiological processes, including electromechanical feedback in the heart, cell volume regulation and perception of shear flow stress in epithelial tissues, pressureinduced vasorelaxation in endothelia, and even cell migration (25)(26)(27)(28). Crystal structures are also now available for these three channels in multiple conformations (29)(30)(31)(32); thus, they provide an excellent opportunity to investigate the molecular mechanisms underlying mechanosensitivity in eukaryotic ion channels.…”

The Living Scar – Cardiac Fibroblasts and the Injured Heart

“…Examples include voltage-gated K + channels, inward rectifying K + channels, large-conductance Ca 2+ -activated K + channels, chloride channels (including cell-volume activated channels), voltage-gated proton channels, sodium-calcium exchangers, sodium-potassium ATPases, and stretch-activated channels [90–92]. The latter include BK Ca , K ATP , and cation-nonselective stretch-activated channels, as well as the more recently described transient potential receptor family of ion channels such as TRPM7 [93], TRPV4 [93], and TRPC6 [94] (reviewed in detail elsewhere: [95, 96]).…”

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

“…These cardioprotective effects may be due to improved blood flow to ischemic tissue during hypoxia since GsMTx4 causes vascular smooth muscle relaxation by both decreasing mechanically activated excitatory cation currents [110, 111] and down regulation of endothelin-1 stimulated increase in arterial resistance [112, 113]. It may also affect fibroblast conductive properties which are known to play a role in generation of arrhythmias following ischemia [114, 115]. In this regard GsMTx4’s potentiation of K2P and SAKCa channels may also be important aspects of its antiarrhythmic effect.…”