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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Tachykinin Receptor Expression and Function in Human Esophageal Smooth Muscle

Departments of Physiology and Pharmacology (J.R.K., T.C., H.G.P., S.M.S.) and Medicine (H.G.P.), Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada

Tachykinins are present in enteric nerves of the gastrointestinal tract and cause contraction of esophageal smooth muscle; however, the mechanisms involved are not understood. Our aim was to characterize tachykinin signaling in human esophageal smooth muscle. We investigated functional effects of tachykinins on human esophageal smooth muscle using tension recordings and isolated cells, receptor expression with reverse transcription (RT)-polymerase chain reaction (PCR) and immunoblotting, intracellular Ca²⁺ responses using fluorescent indicator dyes, and membrane currents with patch-clamp electrophysiology. The mammalian tachykinins [substance P and neurokinin (NK) A and NKB] elicited concentration-dependent contractions of human esophageal smooth muscle. These responses were not affected by muscarinic receptor or neuronal blockade indicating a direct effect on smooth muscle cells (SMCs). Immunofluorescence and RT-PCR identified tachykinin receptors (NK1, NK2, and NK3) on SMCs. Contraction was mediated through a combination of Ca²⁺ release from intracellular stores and influx through L-type Ca²⁺ channels. NK2 receptor blockade inhibited the largest proportion of tachykinin-evoked responses. NKA evoked a nonselective cation current (I_NSC) with properties similar to that elicited by muscarinic stimulation. The following paradigm is suggested: tachykinin receptor binding to SMCs releases Ca²⁺ from stores along with activation of I_NSC, which in turn results in membrane depolarization, L-type Ca²⁺ channel opening, rise of Ca²⁺ concentration, and contraction. These studies reveal new aspects of tachykinin signaling in human esophageal SMCs. Excitatory tachykinin pathways may represent targets for pharmacological intervention in disorders of esophageal dysmotility.

Address correspondence to: Dr. Stephen M. Sims, Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada N6A 5C1. E-mail: stephen.sims{at}schulich.uwo.ca

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