Multiple intracellular signaling pathways of the neuropeptide substance P receptor

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Abstract
The rat substance P (SP) receptor cDNA has been transfected into cultured rat KNRK cells, and a stable cell line expressing functional SP receptors established. Upon stimulation with SP, these cells responded by simultaneously activating two signaling pathways: the mobilization of intracellular Ca2+ and the raising of cyclic adenosine triphosphate (cAMP) levels. Both Ca2+ and cAMP responses were elicited in a similar dose‐dependent manner with half maximal concentrations of approximately 5 × 10−10 M. Following ionomycin treatment SP‐dependent Ca2+ responses were abolished, whereas cAMP responses were preserved. Forskolin eliminated the SP‐dependent cAMP elevation, however, the SP‐induced Ca2+ mobilization remained unchanged. Furthermore, treatment with phorbol esters had no significant effect on either of the two SP‐induced responses. Thus it appears that the SP receptor is capable of independently activating Ca2+ mobilization and cAMP pathways. These results may provide new insights for further understanding the diverse activities of SP in various systems in vitro and in vivo.