Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process. Here, we show that loss of the mechanosensitive channels TMEM63A and TMEM63B (TMEM63A/B) resulted in atelectasis and respiratory failure in mice due to a deficit of surfactant secretion. TMEM63A/B were predominantly localized at the limiting membrane of the lamellar body (LB), a lysosome-related organelle that stores pulmonary surfactant and ATP in AT2 cells. Activation of TMEM63A/B channels during cell stretch facilitated the release of surfactant and ATP from LBs fused with the plasma membrane. The released ATP evoked Ca²⁺ signaling in AT2 cells and potentiated exocytic fusion of more LBs. Our study uncovered a vital physiological function of TMEM63 mechanosensitive channels in preparing the lungs for the first breath at birth and maintaining respiration throughout life.

Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by binding and activating the three G protein-coupled receptors (S1PR1, S1PR2, and S1PR3) expressed in endothelial and smooth muscle cells, as well as cardiomyocytes and fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, and apoptosis. S1P is essential for the development of the cardiovascular system, and abnormal S1P content in the circulation is involved in the pathogenesis of cardiovascular disorders. This article reviews the effects of S1P on cardiovascular function and signaling mechanisms in different cell types in the heart and blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators and the development of S1P-based therapies for cardiovascular diseases.

JOURNAL/nrgr/04.03/01300535-202306000-00023/inline-graphic1/v/2022-11-21T174919Z/r/image-tiff

Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to play important roles in many physiological processes and diseases such as developmental disorders, neurodegenerative diseases, and cancer. However, in the field of ion channel discovery, there are an unignorable number of published studies that are unsolid and misleading. Despite being the gold standard of a functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance, and background currents of the membrane system. These unwanted signals, if not treated properly, lead to the mischaracterization of proteins with seemingly unusual ion-conducting properties. In the recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) has greatly advanced our understanding of the structures and gating mechanisms of various ion channels and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function. We propose that cross-validation by electrophysiological and structural analyses should be essentially required for determining molecular identities of novel ion channels.

An elevated level of circulating homocysteine (Hcy) has been regarded as an independent risk factor for cardiovascular disease; however, the clinical benefit of Hcy lowering-therapy is not satisfying. To explore potential unrevealed mechanisms, we investigated the roles of Ca²⁺ influx through TRPC channels and regulation by Hcy–copper complexes. Using primary cultured human aortic endothelial cells and HEK-293 T-REx cells with inducible TRPC gene expression, we found that Hcy increased the Ca²⁺ influx in vascular endothelial cells through the activation of TRPC4 and TRPC5. The activity of TRPC4 and TRPC5 was regulated by extracellular divalent copper (Cu²⁺) and Hcy. Hcy prevented channel activation by divalent copper, but monovalent copper (Cu⁺) had no effect on the TRPC channels. The glutamic acids (E542/E543) and the cysteine residue (C554) in the extracellular pore region of the TRPC4 channel mediated the effect of Hcy–copper complexes. The interaction of Hcy–copper significantly regulated endothelial proliferation, migration, and angiogenesis. Our results suggest that Hcy–copper complexes function as a new pair of endogenous regulators for TRPC channel activity. This finding gives a new understanding of the pathogenesis of hyperhomocysteinemia and may explain the unsatisfying clinical outcome of Hcy-lowering therapy and the potential benefit of copper-chelating therapy.