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The Journal of Neuroscience, February 1, 1999, 19(3):890-899

G-Proteins Are Involved in 5-HT Receptor-Mediated Modulation of N- and P/Q- But Not T-Type Ca²⁺ Channels

Qian-Quan Sun and Nicholas Dale

School of Biomedical Sciences, University of St. Andrews, Scotland KY16 9TS, United Kingdom

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-HT_1A and 5-HT_1D 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--S (2 mM), GTP--S (200 µM), 5'-guanylyl-imidodiphosphate tetralithium (200 µM), aluminum fluoride (AlF₄, 100 µM), 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-HT_1A and 5-HT_1D 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.

Key words: G-proteins; 5-HT; N-type Ca²⁺ channels; P/Q-type Ca²⁺ channels; T-type Ca²⁺ channels; receptor-derived peptide; Xenopus

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Copyright © 1999 Society for Neuroscience  0270-6474/99/193890-10$05.00/0

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