Modulation of nicotinic ACh-, GABAA- and 5-HT3-receptor functions by external H-7, a protein kinase inhibitor, in rat sensory neurones

Br J Pharmacol. 1997 Nov;122(6):1195-201. doi: 10.1038/sj.bjp.0701462.

Abstract

1. The effects of external H-7, a potent protein kinase inhibitor, on the responses mediated by gamma-aminobutyric acid A type (GABAA)-, nicotinic acetylcholine (nicotinic ACh)-, ionotropic 5-hydroxytryptamine (5-HT3)-, adenosine 5'-triphosphate (ATP)-, N-methyl-D-aspartate (NMDA)- and kainate (KA)-receptors were studied in freshly dissociated rat dorsal root ganglion neurone by use of whole cell patch-clamp technique. 2. External H-7 (1-1000 microM) produced a reversible, dose-dependent inhibition of whole cell currents activated by GABA, ACh and 5-HT. 3. Whole-cell currents evoked by ATP, 2-methylthio-ATP, NMDA and KA were insensitive to external H-7. 4. External H-7 shifted the dose-response curve of GABA-activated currents downward without changing the EC50 significantly (from 15.0 +/- 4.0 microM to 18.0 +/- 5.0 microM). The maximum response to GABA was depressed by 34.0 +/- 5.3%. This inhibitory action of H-7 was voltage-independent. 5. Intracellular application of H-7 (20 microM), cyclic AMP (1 mM) and BAPTA (10 mM) could not reverse the H-7 inhibition of GABA-activated currents. 6. The results suggest that external H-7 selectively and allosterically modulates the functions of GABAA-, nicotine ACh- and 5-HT3 receptors via a common conserved site in the external domain of these receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology*
  • Acetylcholine / pharmacology
  • Adenosine Triphosphate / pharmacology
  • Allosteric Regulation
  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Kainic Acid / pharmacology
  • Membrane Potentials / drug effects
  • N-Methylaspartate / pharmacology
  • Neurons, Afferent / drug effects*
  • Neurons, Afferent / metabolism
  • Protein Kinase Inhibitors*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects*
  • Receptors, Nicotinic / drug effects*
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin, 5-HT3
  • Second Messenger Systems / drug effects
  • Serotonin / pharmacology
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Receptors, GABA-A
  • Receptors, Nicotinic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin
  • gamma-Aminobutyric Acid
  • N-Methylaspartate
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Adenosine Triphosphate
  • Acetylcholine
  • Kainic Acid