Regulation of K⁺ and Ca⁺⁺ channels by a family of neuropeptide Y receptors

We examined the ability of rat Y1, Y2 and Y4 neuropeptide Y (NPY) receptors to regulate K⁺ and Ca⁺⁺ channels expressed in Xenopus oocytes and HEK 293 cells, respectively. Stimulation of all three receptors with NPY or related peptides activated inwardly rectifying K⁺ currents resulting from the expression of rat GIRK1/CIR in frog oocytes. These effects were inhibited by pertussis toxin treatment. The effects of activating Y1 receptors were antagonized competitively by BIBP3226, SR120819A and GW1229. The effects of Y2 receptor activation were not blocked by these drugs, and the effects of Y4 receptor activation were only blocked by GW1229. Activation of all three NPY receptors also inhibited human alpha-1B Ca⁺⁺ channels stably expressed in HEK293 cells. The effects of agonists at all three receptors were blocked by pertussis toxin treatment and were voltage dependent. Activation of all three types of NPY receptors produced much smaller inhibition of human alpha-1E Ca⁺⁺ channels also stably expressed in HEK293 cells. These results suggest that NPY receptors can regulate K⁺ and Ca⁺⁺ channels and that these effects may be responsible for the observed effects of NPY on neuronal excitability and synaptic transmission.