TRIC channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca(2+) release from internal stores. Tric-a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca(2+) release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca(2+) sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP(3)Rs) evokes global Ca(2+) transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca(2+) influx, and adversely enhanced IP(3)R-mediated Ca(2+) transients by overloading Ca(2+) stores in VSMCs. Moreover, association analysis identified single-nucleotide polymorphisms (SNPs) around the human TRIC-A gene that increase hypertension risk and restrict the efficiency of antihypertensive drugs. Therefore, TRIC-A channels contribute to maintaining blood pressure, while TRIC-A SNPs could provide biomarkers for constitutional diagnosis and personalized medical treatment of essential hypertension.

Yamamoto, Shintaro, and Tsuguhisa Ehara. Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes. Am J Physiol Heart Circ Physiol 290: H1905-H1914, 2006. First published December 9, 2005 doi:10.1152/ajpheart.00965.2005.-Extracellular acidic pH was found to induce an outwardly rectifying Cl Ϫ current (ICl,acid) in mouse ventricular cells, with a half-maximal activation at pH 5.9. The current showed the permeability sequence for anions to be SCN Ϫ Ͼ Br Ϫ Ͼ I Ϫ Ͼ Cl Ϫ Ͼ F Ϫ Ͼ aspartate, while it exhibited a time-dependent activation at large positive potentials. Similar currents were also observed in mouse atrial cells and in atrial and ventricular cells from guinea pig. Some Cl Ϫ channel blockers (DIDS, niflumic acid, and glibenclamide) inhibited I Cl,acid, whereas tamoxifen had little effect on it. Unlike volume-regulated Cl Ϫ current (I Cl,vol) and CFTR Cl Ϫ current (ICl,CFTR), ICl,acid was independent of the presence of intracellular ATP. Activation of I Cl,acid appeared to be also independent of intracellular Ca 2ϩ and G protein. ICl,acid and I Cl,vol could develop in an additive fashion in acidic hypotonic solutions. Isoprenaline-induced I Cl,CFTR was inhibited by acidification in a pH-dependent manner in guinea pig ventricular cells. Our results support the view that I Cl,acid and ICl,vol stem from two distinct populations of anion channels and that the I Cl,acid channels are present in cardiac cells. I Cl,acid may play a role in the control of action potential duration or cell volume under pathological conditions, such as ischemia-related cardiac acidosis. acidosis; chloride channel; heart CHLORIDE (Cl Ϫ ) channels play a role in a variety of cell functions, such as cell cycle, apoptosis, ion homeostasis, cell volume regulation, and muscle tone (for review see Refs. 11,12,and 20). Several types of Cl Ϫ currents have been recorded in native cardiac cells (for review see Refs. 9 and 11). These include Cl Ϫ currents activated by intracellular PKA (I Cl,PKA ), PKC (I Cl,PKC ), Ca 2ϩ (I Cl,Ca ), extracellular ATP (I Cl,ATP ), or cell swelling (I Cl,vol ) and an inwardly rectifying Cl Ϫ current (I Cl,ir ). The channels responsible for I Cl,PKA , I Cl,PKC , and I Cl,ATP likely share the same molecular basis derived from CFTR gene, and thus these currents can be unified as I Cl,CFTR (11). It has been shown that some of these Cl Ϫ currents depend on extracellular pH (pH o ). Acidic pH o enhances I Cl,Ca in rabbit ventricular cells (10) and I Cl,ir in rat atrial and ventricular cells (13,14) and inhibits I Cl,CFTR in guinea pig ventricular cells (17). The roles of such pH o -dependent attenuation of Cl Ϫ currents in cardiac electrical activity under pathophysiological conditions have been investigated (9 -11, 13, 14).On the other hand, a more directly pH o -dependent regulation has been found in cultured cells. Auzanneau et al. (1) Recently, however, Lambert and Oberwinkler (15) extensively studied the properties of I Cl,acid and I Cl,vol in HEK293 cells. Their import...

Background: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. Objective: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients Methods: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. Results: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. Conclusions: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.

The strong inward rectifier K + (K IR ) channel provides one of the major components of the repolarizing outward current, I K1 , in the cardiac action potential (AP). I K1 exhibits voltage-and time-dependent changes because of the blocking kinetics exerted by the intracellular polyamines and Mg

Abstract:The effects of the activation of cyclic AMP-dependent Cl Ϫ current (I Cl,cAMP ) on cell volume were studied at various [K

Abstract. Cardiac hypertrophy is an increase in the muscle volume of the ventricle due to the enlargement of cardiac cells. Physiological cardiac hypertrophy is the normal response to healthy exercise, and pathological hypertrophy is the response to increased stress such as hypertension. Intracellular and extracellular aniosmotic conditions also change cell volume. Since persistent cell swelling or cell shrinkage during aniosmotic conditions results in cell death, the ability to regulate cell volume is important for the maintenance of cellular homeostasis. Cell swelling activates a regulatory volume decrease (RVD) response in which solute leakage pathways are stimulated and solute with water exits cells, reducing the cell volume towards the original value. In cardiac cells, one of the essential factors for cell-volume regulation is the volume-regulated anion channel (VRAC). However, the relationship between cardiac hypertrophy and cell-volume regulation is not clear. In this review, we introduce our recent findings showing that the impairment of VRAC current is exhibited in ventricular cells from mice with cardiac hypertrophy induced by transverse aortic constriction. Similar results were shown in caveolin-3-deficient mice, which develop cardiac hypertrophy without pressure overload. These results suggest that VRAC will be a new target for protection from the development of cardiac hypertrophy.

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