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EDITORIAL FOCUS

Functional TRPV4 channels are expressed in human airway smooth muscle cells

Neurobiology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033

Submitted 17 November 2003 ; accepted in final form 5 April 2004

Hypotonic stimulation induces airway constriction in normal and asthmatic airways. However, the osmolarity sensor in the airway has not been characterized. TRPV4 (also known as VR-OAC, VRL-2, TRP12, OTRPC4), an osmotic-sensitive cation channel in the transient receptor potential (TRP) channel family, was recently cloned. In the present study, we show that TRPV4 mRNA was expressed in cultured human airway smooth muscle cells as analyzed by RT-PCR. Hypotonic stimulation induced Ca²⁺ influx in human airway smooth muscle cells in an osmolarity-dependent manner, consistent with the reported biological activity of TRPV4 in transfected cells. In cultured muscle cells, 4-phorbol 12,13-didecanoate (4-PDD), a TRPV4 ligand, increased intracellular Ca²⁺ level only when Ca²⁺ was present in the extracellular solution. The 4-PDD-induced Ca²⁺ response was inhibited by ruthenium red (1 µM), a known TRPV4 inhibitor, but not by capsazepine (1 µM), a TRPV1 antagonist, indicating that 4-PDD-induced Ca²⁺ response is mediated by TRPV4. Verapamil (10 µM), an L-type voltage-gated Ca²⁺ channel inhibitor, had no effect on the 4-PDD-induced Ca²⁺ response, excluding the involvement of L-type Ca²⁺ channels. Furthermore, hypotonic stimulation elicited smooth muscle contraction through a mechanism dependent on membrane Ca²⁺ channels in both isolated human and guinea pig airways. Hypotonicity-induced airway contraction was not inhibited by the L-type Ca²⁺ channel inhibitor nifedipine (1 µM) or by the TRPV1 inhibitor capsazepine (1 µM). We conclude that functional TRPV4 is expressed in human airway smooth muscle cells and may act as an osmolarity sensor in the airway.

calcium influx; fluorometric imaging plate reader; hypotonic solution; smooth muscle contraction; vanilloid receptor-related osmotically activated channel

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