G-proteins are involved in 5-HT receptor-mediated modulation of N- and P/Q- but not T-type Ca2+ channels.

5-HT produces voltage-independent inhibition of the N-, P/Q-, and T-type Ca2+ currents in sensory neurons of Xenopus larvae by acting on 5-HT1A and 5-HT1D receptors. We have explored the underlying mechanisms further and found that the inhibition of high voltage-activated (HVA) currents by 5-HT is mediated by a pertussis toxin-sensitive G-protein that activates a diffusible second messenger. Although modulation of T-type currents is membrane-delimited, it was not affected by GDP-beta-S (2 mM), GTP-gamma-S (200 microM), 5'-guanylyl-imidodiphosphate tetralithium (200 microM), aluminum fluoride (AlF4-, 100 microM), or pertussis toxin, suggesting that a GTP-insensitive pathway was involved. To investigate the modulation of the T currents further, we synthesized peptides that were derived from conserved cytoplasmic regions of the rat 5-HT1A and 5-HT1D receptors. Although two peptides derived from the third cytoplasmic loop inhibited the HVA currents by activating G-proteins and occluded the modulation of HVA currents by 5-HT, two peptides from the second cytoplasmic loop and the C tail had no effect. None of the four receptor-derived peptides had any effect on the T-type currents. We conclude that 5-HT modulates T-type channels by a membrane-delimited pathway that does not involve G-proteins and is mediated by a functional domain of the receptor that is distinct from that which couples to G-proteins.