Differential effects of protein kinase C activation on 5-HT1A receptor coupling to Ca2+ and K+ currents in rat serotonergic neurones

J Physiol. 1996 Oct 1;496 ( Pt 1)(Pt 1):129-37. doi: 10.1113/jphysiol.1996.sp021670.

Abstract

1. Activation of the enzyme protein kinase C (PKC) partially uncouples receptors from the inhibition of Ca2+ current. We have studied the effect of PKC activation on 5-HT1A receptor coupling of Ca2+ currents and 5-HT-induced K+ current (IK,5-HT) in acutely isolated adult rat dorsal raphe neurones. 2. The phorbol ester 4 beta-phorbol 12-myristate, 13-acetate (PMA; 1 microM) did not significantly alter the peak Ca2+ current. A maximal dose of 5-HT inhibited Ca2+ current on average by 52%; after application of PMA, the inhibition was only 30% and the effect was irreversible for the duration of the experiment. 3. The inactive phorbol ester 4 alpha-phorbol (1 microM) did not reduce the effectiveness of 5-HT. When the kinase inhibitor staurosporine (ST; 200 nM) was added, PMA reduced the effect of 5-HT by only 13.9%. ST partially prevented or reversed the effect of PMA, depending on the order of addition. 4. The voltage-dependent rate or re-inhibition by 5-HT was reduced by PMA, suggesting that fewer activated G-protein subunits are available to interact with Ca2+ channel after the action of PMA. 5. In contrast, PMA (1 microM) did not have a significant effect on IK,5-HT. 6. PKC activation has an inhibitory effect on one branch of the 5-HT1A receptor transduction fork, namely inhibition of Ca2+ influx, but not on the activation of IK,5-HT.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism*
  • Enzyme Activation / drug effects
  • GTP-Binding Proteins / metabolism
  • In Vitro Techniques
  • Male
  • Neurons / drug effects
  • Neurons / metabolism*
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Raphe Nuclei / cytology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism*
  • Serotonin / physiology*
  • Signal Transduction / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Potassium Channels
  • Receptors, Serotonin
  • Serotonin
  • Protein Kinase C
  • GTP-Binding Proteins
  • Tetradecanoylphorbol Acetate