title: Regulation of the cardiac Na⁺/H⁺ exchanger in health and disease.
abstract: The Na(+) gradient produced across the cardiac sarcolemma by the ATP-dependent Na(+)-pump is a constant source of energy for Na(+)-dependent transporters. The plasma membrane Na(+)/H(+) exchanger (NHE) is one such secondary active transporter, regulating intracellular pH, Na(+) concentration, and cell volume. NHE1, the major isoform found in the heart, is activated in response to a variety of stimuli such as hormones and mechanical stress. This important characteristic of NHE1 is intimately linked to heart diseases, including maladaptive cardiac hypertrophy and subsequent heart failure, as well as acute ischemic-reperfusion injury. NHE1 activation results in elevation of pH and intracellular Na(+) concentration, which potentially enhance downstream signaling cascades in the myocardium. Therefore, in addition to determining the mechanism underlying regulation of NHE1 activity, it is important to understand how the ionic signal produced by NHE1 is transmitted to the downstream targets. Extensive studies have identified many accessory factors that interact with NHE1. Here, we have summarized the recent progress on understanding the molecular mechanism underlying NHE1 regulation and have shown a possible signaling pathway leading to cardiac remodeling, which is initiated from NHE1. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".
authors: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. wak@ri.ncvc.go.jp
authors: Shigeo
authors: S
authors: Wakabayashi
authors: Takashi
authors: T
authors: Hisamitsu
authors: Tomoe Y
authors: TY
authors: Nakamura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D019703:Calcineurin
keywords: CHP; Ca(2+)/CaM-dependent protein kinase II; CaM; CaMKII; CaN; Calcineurin; Calcineurin B homologous protein; Calmodulin; Cardiac hypertrophy; DAG; HDAC; Hormonal regulation; IP(3); LID; NCX; NFAT; NHE; Na(+)/Ca(2+) exchanger; Na(+)/H(+) exchanger; PIP(2); PIP(3); SHR; TM; calcineurin; calcineurin B homologous protein; calmodulin; diacylglycerol; histone deacetylase; inositol 1,4,5-trisphosphate; intracellular pH; lipid-interacting domain; nuclear factor of activated T cells; pH(i); phosphatidylinositol (3,4,5)-trisphosphate; phosphatidylinositol 4,5-bisphosphate; spontaneously hypertensive rat; transmembrane