59341

TRPV4

CMT2C|HMSN2C|OTRPC4|SMAL|SPSMA|SSQTL1|TRP12|VRL2|VROAC;transient receptor potential cation channel, subfamily V, member 4;TRPV4;transient receptor potential cation channel, subfamily V, member 4

OSM9-like transient receptor potential channel 4|osm-9-like TRP channel 4|osmosensitive transient receptor potential channel 4|transient receptor potential cation channel subfamily V member 4|transient receptor potential protein 12|vanilloid receptor-like

12q24.1

protein-coding

Count: Trpv4; 66026

There is a growing body of evidence indicating that transient receptor potential (TRP) channels are implicated in calcium signaling and various cellular functions in the pulmonary vasculature. The aim of this study was to investigate the expression, functional role, and coupling to reticulum calcium channels of the type 4 vanilloid TRP subfamily (TRPV4) in the pulmonary artery from both normoxic (Nx) and chronically hypoxic (CH) rats. Activation of TRPV4 with the specific agonist 4alpha-phorbol-12,13-didecanoate (4alpha-PDD, 5 muM) increased the intracellular calcium concentration ([Ca(2+)](i)). This effect was significantly reduced by a high concentration of ryanodine (100 muM) or chronic caffeine (5 mM) that blocked ryanodine receptor (RyR) but was insensitive to xestospongin C (10 muM), an inositol trisphosphate receptor antagonist. Inhibition of RyR1 and RyR3 only with 10 muM of dantrolene did not attenuate the 4alpha-PDD-induced [Ca(2+)](i) increase. Western blotting experiments revealed the expression of TRPV4 and RyR2 with an increase in both receptors in pulmonary arteries from CH rats vs. Nx rats. Accordingly, the 4alpha-PDD-activated current, measured with patch-clamp technique, was increased in pulmonary artery smooth muscle cells (PASMC) from CH rats vs. Nx rats. 4alpha-PDD increased isometric tension in artery rings, and this response was also potentiated under chronic hypoxia conditions. 4alpha-PDD-induced calcium response, current, and contraction were all inhibited by the selective TRPV4 blocker HC-067047. Collectively, our findings provide evidence of the interplay between TRPV4 and RyR2 in the Ca(2+) release mechanism and contraction in PASMC. This study provides new insights onto the complex calcium signaling in PASMC and point out the importance of the TRPV4-RyR2 signaling pathway under hypoxic conditions that may lead to pulmonary hypertension.