Mechanisms involved in carbachol-induced Ca(2+) sensitization of contractile elements in rat proximal and distal colon

Br J Pharmacol. 2004 Jun;142(4):657-66. doi: 10.1038/sj.bjp.0705820. Epub 2004 May 24.

Abstract

1. Mechanisms involved in Ca(2+) sensitization of contractile elements induced by the activation of muscarinic receptors in membrane-permeabilized preparations of the rat proximal and distal colon were studied. 2. In alpha-toxin-permeabilized preparations from the rat proximal and distal colon, Ca(2+) induced a rapid phasic and subsequent tonic component. After Ca(2+)-induced contraction reached a plateau, guanosine 5'-triphosphate (GTP) and carbachol (CCh) in the presence of GTP further contracted preparations of both the proximal and distal colon (Ca(2+) sensitization). Y-27632, a rho-kinase inhibitor, inhibited GTP plus CCh-induced Ca(2+) sensitization more significantly in the proximal colon than in the distal colon. 3. Y-27632 at 10 microm had no effect on Ca(2+)-induced contraction or slightly inhibited phorbol-12,13-dibutyrate-induced Ca(2+) sensitization in either proximal or distal colon. Chelerythrine, a protein kinase C inhibitor, inhibited GTP plus CCh-induced Ca(2+) sensitization in the distal colon, but not in the proximal colon. The component of Ca(2+) sensitization that persisted after the chelerythrine treatment was completely inhibited by Y-27632. 4. In beta-escin-permeabilized preparations of the proximal colon, C3 exoenzyme completely inhibited GTP plus CCh-induced Ca(2+) sensitization, but PKC(19-31) did not. In the distal colon, C3 exoenzyme abolished GTP-induced Ca(2+) sensitization. It inhibited CCh-induced sensitization by 50 % and the remaining component was inhibited by PKC(19-31). 5. These results suggest that both protein kinase C and rho pathways in parallel mediate the Ca(2+) sensitization coupled to activation of muscarinic receptors in the rat distal colon, whereas the rho pathway alone mediates this action in the proximal colon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases / pharmacology
  • Alkaloids
  • Amides / pharmacology
  • Animals
  • Bacterial Toxins / pharmacology
  • Benzophenanthridines
  • Botulinum Toxins / pharmacology
  • Calcium / antagonists & inhibitors
  • Calcium / metabolism*
  • Carbachol / antagonists & inhibitors
  • Carbachol / pharmacology*
  • Cell Membrane Permeability / drug effects
  • Colon, Ascending / drug effects*
  • Colon, Ascending / pathology
  • Colon, Descending / drug effects*
  • Colon, Descending / pathology
  • Escin / pharmacology
  • Guanosine Triphosphate / antagonists & inhibitors
  • Guanosine Triphosphate / pharmacology
  • Hemolysin Proteins / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Japan
  • Male
  • Muscle Contraction / drug effects
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / physiology
  • Peptide Fragments / pharmacology
  • Phenanthridines / antagonists & inhibitors
  • Phenanthridines / pharmacology
  • Phorbol 12,13-Dibutyrate / pharmacology
  • Protein Kinase C / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Muscarinic / drug effects
  • Tritium
  • Type C Phospholipases / pharmacology
  • rho-Associated Kinases

Substances

  • Alkaloids
  • Amides
  • Bacterial Toxins
  • Benzophenanthridines
  • Hemolysin Proteins
  • Intracellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Phenanthridines
  • Pyridines
  • Receptors, Muscarinic
  • protein kinase C (19-31)
  • staphylococcal alpha-toxin
  • Tritium
  • Y 27632
  • Phorbol 12,13-Dibutyrate
  • Escin
  • Guanosine Triphosphate
  • Carbachol
  • chelerythrine
  • ADP Ribose Transferases
  • exoenzyme C3, Clostridium botulinum
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Protein Kinase C
  • Type C Phospholipases
  • Botulinum Toxins
  • Calcium