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, is 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 intracardially and are, thus, maintained even in heart transplant recipients. Although mechanosensitivity 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 mechanotransduction have started to emerge. Mechano-gated ion channels are cardiac mechanoreceptors. 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.

Keywords: cardiac electrophysiology; heart rhythm; mechanotransduction.

Figure 1

MGC and mechanically modulated channel (MMC) candidates are present throughout living organisms. Several mammalian channels have homologues in other organisms: e.g. NOMPC, OSM9, TRP4, TRPY1 and LOV-1 are TRP homologues; MEC channels are members of the DEG/ENaC superfamily whose mammalian representatives are ASIC channels; TPK is a homologue of K_2P channels; Mid1 is homologous to voltage-gated calcium channels. In red: channels expressed in the heart; underlined: channels clearly identified as MGC; channels with no known mammalian homologues are marked by *. “SAC_NS”: stretch-activated channels, cation non selective; “SAC_K”: stretch-activated channels, potassium selective; “Mito”: mitochondria; “SR”: sarcoplasmic reticulum. Only a selection of the more well-known channels and receptors is presented; protein names for mammals are explained in Section 2.

Figure 2

Mechanically Modulated Channels (MMC) versus Mechanically Gated Channels (MGC). Presentation includes channels understood to be activated by transmembrane voltage, ligands, stretch (SAC: Stretch Activated Channel) or intracellular volume change (VAC: Volume Activated Channel). In red: channels expressed in the heart.

Figure 3

Stretch greatly modifies the action potential (AP). Representative recordings showing the effect of stretch intensity on AP and resting membrane potential in single isolated cardiomyocytes. Stretch was applied during the entire duration of recordings, scaled to control cell length (left: moderate stretch, right: large stretch); control recordings: black; stretch: red. Red arrows indicate putative contributions of SAC_NS, blue arrows represent potential effects of SAC_K. Adapted from Kohl et al.

Figure 4

size matters. Strain is greatly influenced by size and shape of affected structures, and spans all scales from nano to macro. Tools to study mechano-sensors are listed on the left in parallel with milestones. Membrane (blue), cytoskeleton (red), measuring probes (green), others structures (black) are annotaed. MRI: Magnetic Resonance Imaging, AFM: Atomic Fore Microscopy, Ø: diameter.