The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the “regulins”. Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA—formed by transmembrane helices M2, M6, and M9—can result in distinct functional outcomes.

SUMMARY PARAGRAPH: Maintenance of cardiac function involves a regulatory loop in which electrical excitation causes the heart to contract through excitation-contraction coupling (ECC), ¹ and the mechanical state of the heart directly affects its electrical activity through mechano-electric coupling (MEC). ² However, in pathological states such as acute ischaemia that alter early or late electro-mechanical coordination ( i.e. , disturbances in ECC or repolarisation-relaxation coupling, RRC), MEC may contribute to the initiation and / or sustenance of arrhythmias (mechano-arrhythmogenesis). ³ The molecular identity of specific factor(s) underlying mechano-arrhythmogenesis in acute ischaemia, however, remain undefined. ⁴ By rapid stretch of rabbit single left ventricular cardiomyocytes, we show that upon ATP-sensitive potassium channel-induced alterations of RRC, overall vulnerability to mechano-arrhythmogenesis is increased, with mechano-sensitive ^5–11 transient receptor potential kinase ankyrin 1 (TRPA1) channels ¹² acting as the molecular driver through a Ca ²⁺ -mediated mechanism. Specifically, TRPA1 activation drives stretch-induced excitation and creates a substrate for self-sustained arrhythmias, which are maintained by increased cytosolic free Ca ²⁺ concentration ([Ca ²⁺ ] _i ) and spontaneous [Ca ²⁺ ] _i oscillations. This TRPA1-dependent mechano-arrhythmogenesis involves microtubules, and can be prevented by block of TRPA1 or buffering of [Ca ²⁺ ] _i . Thus, in cardiac pathologies with disturbed RRC dynamics and / or augmented TRPA1 activity, TRPA1 may represent an anti-arrhythmic target with untapped therapeutic potential. ^13–17