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Substance P Evokes Cation Currents Through TRP Channels in HEK293 Cells

¹ Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore, Maryland 21201-1559 ² Neuroscience Program, University of Maryland Medical School, Baltimore, Maryland 21201-1559

Submitted 13 January 2003; accepted in final form 30 April 2003

Activation of any of the three known tachykinin receptors (NK1R, -2R, or -3R) can cause a rise in [Ca²⁺]_i via a pertussis toxin-insensitive heterotrimeric G protein, G_q/G₁₁, activation of phospholipase C (PLC), and a membrane depolarization. Tachykinins can depolarize neurons by two distinct mechanisms: 1) they reduce a resting K⁺ current in many neurons or 2) in parasympathetic and vagal primary sensory neurons, they activate a nonspecific cation current (I_cat). Transient receptor potential channels (TRPC) are nonspecific cation channels that can be activated by a rise in [Ca²⁺]_i in a PLC-dependent manner. The present work tests whether NK2R can signal TRPC. We applied standard whole cell patch-clamp recordings to HEK293 cells stably transfected with the human TRP3 channels (TRP3C), and transiently transfected with a functional NK2R-EGFP. Bath applied Substance P (SP, 1 µM) induced an I_cat in the cells expressing both TRP3C and NK2R. I_cat reached its peak value in approximately 3 min (195 ± 120.0 s, mean ± SE, n = 20), had a peak density of 11.3 ± 3.48 pA/pF (n = 24), and was blocked by an NK2R-specific antagonist (SR48968, 100 nM). The E_rev value for the SP current was 6.8 ± 7.66 mV (n = 6), suggestive of a nonspecific cation channel. I_cat was not measurable in TRP3C-expressing HEK293 cells without NK2R expression (n = 6) or in wild-type HEK293 cells with NK2R expression (n = 12). These data indicate that NK2R can be functionally coupled to TRP channels in HEK293 cells and suggest that SP-induced cation currents in vagal primary sensory neurons might be mediated by TRPC.

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