Protein Kinase C Is Involved in Neurokinin Receptor Modulation of N- and L-Type Ca2+Channels in DRG Neurons of the Adult Rat

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Abstract
Whole cell patch-clamp techniques were used to examine neurokinin receptor modulation of Ca2+channels in small to medium size dorsal root ganglia neurons (2+currents. Low concentrations of substance P enhanced Ca2+currents (5–40%, 0.5 μM). This apparent inhibition by high concentrations of substance P was blocked by the administration of the NK3antagonist SB 235,375 (0.2 μM). The NK1agonist, [Sar9,Met11]-substance P (0.05 to 1.0 μM) did not alter Ca2+currents; whereas the NK2agonist, [βAla8]-neurokinin A (4–10), enhanced Ca2+currents (5–36% increase, 0.05–0.5 μM). The enhancement was reversed by the NK2antagonist MEN 10,376 (0.2 μM) but unaffected by the NK3antagonist SB 235,375 (0.2 μM). The NK3agonist [MePhe7]-neurokinin B (0.5–1.0 μM) inhibited Ca2+currents (6–24% decrease). This inhibition was not prevented by the NK2antagonist MEN 10,376 (0.2 μM) but was blocked by the NK3antagonist SB 235,375 (0.2 μM). Both the enhancement and inhibition of Ca2+currents by neurokinin agonists were reversed by the protein kinase C inhibitor bisindolylmaleimide I HCl (0.2–0.5 μM). Following inhibition of Ca2+channels by [MePhe7]-neurokinin the facilitatory effect of BayK 8644 (5 μM) was increased and the inhibitory effect of the N-type Ca2+channel blocker w -conotoxin GVIA (1 μM) was diminished, suggesting that the NK3agonist inhibits N-type Ca2+channels. Similarly, block of all but N-type Ca2+channels, revealed that [βAla8]-neurokinin A (4–10) enhanced the currents while [MePhe7]-neurokinin B inhibited the currents. Inhibition of all but L-type Ca2+channels, revealed that [βAla8]-neurokinin A (4–10) enhanced the currents while [MePhe7]-neurokinin B had no effect. Activation of protein kinase C with low concentrations of phorbol-12,13-dibutyrate enhanced Ca2+currents, but high concentrations inhibited N- and L-type Ca2+currents. In summary, these data suggest that in adult rat dorsal root ganglia neurons, NK2receptors enhance both L- and N-type Ca2+channels and NK3receptors inhibit N-type Ca2+channels and that these effects are mediated by protein kinase C phosphorylation of Ca2+channels.

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