Fig. 7.

Putative model for the intracellular signaling pathways involved in NPY-induced VSMC proliferation. NPY stimulates VSMC proliferation at concentrations ranging from 10⁻¹⁴ to 10⁻⁷ mol·L⁻¹, in a characteristic bimodal fashion with 2 growth peaks — high-affinity (below known NPY receptor K_ds) and low-affinity (10⁻⁹–10⁻⁷ mol·L⁻¹). At all concentrations, NPY activates G_i/o proteins, which stimulate 2 major signaling pathways: Y1 receptor-mediated PLC activation and Y1 and Y5 receptor-mediated inhibition of adenylyl cyclase. PLC activation leads to the increase in intracellular calcium, mainly by extracellular calcium influx, but possibly also by its mobilization from intracellular stores. Increase in calcium activates PKC, which stimulates the Ras–Raf–MEK–ERK1/2 cascade, and CaMKII, which facilitates this by direct interactions with Raf-1. Decrease in adenylyl cyclase activity and cAMP level inhibits PKA and, as a consequence, blocks its inhibitory effects on the Ras and Raf proteins. This pathway is particularly important at low concentrations of NPY, where Y5-dependent PKA inhibition provides additional amplification of Y1 receptor-mediated mitogenic signal.