The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Calpha

Biochim Biophys Acta. 2003 Apr 7;1640(1):85-96. doi: 10.1016/s0167-4889(03)00023-5.

Abstract

The 5-HT(1A) agonist 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) causes inhibition of caspase-3 and apoptosis via the extracellular signal-regulated kinases (ERK1/2) in hippocampal HN2-5 cells. Two 5-HT(1A) agonists, Repinotan hydrochloride (BAY x 3702) and 8-OH-DPAT, block caspase-3 activation and apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment. This is reversed upon transient expression of dominant negative Ras (N17Ras) and Raf-1 (Raf301), confirming the involvement of Ras and Raf-1 in this 5-HT(1A)-R-->ERK1/2-->caspase-3 pathway. A selective inhibitor of phospholipase Cbeta (PLCbeta) (U73122) but not a general protein kinase C (PKC) inhibitor (GFX) reversed the 5-HT(1A)-R-mediated ERK1/2 stimulation. However, both GFX and the PKCalpha and PKCbeta(1) inhibitor Gö6976 reversed the ERK1/2-mediated inhibition of caspase-3. ERK-dependent activation of only PKCalpha was observed in immunoprecipitates obtained from 5-HT(1A) agonist-treated HN2-5 cells. Finally, transient expression of kinase-negative PKCalpha eliminated the 8-OH-DPAT-evoked block on the H(2)O(2)-triggered caspase-3 stimulation, establishing PKCalpha as a link between ERK and caspase-3 (5-HT(1A)-R-->PLC-->ERK1/2-->PKCalpha-->caspase-3). Our results elucidate a novel yet general, neuroprotective pathway through which G protein-coupled receptors could cause inhibition of effector caspases, such as caspase-3.

Publication types

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

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Apoptosis
  • Benzopyrans
  • Calcium / metabolism
  • Caspase 3
  • Caspase Inhibitors*
  • Cell Line
  • Enzyme Activation
  • Hydrogen Peroxide
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neuroprotective Agents
  • Protein Kinase C / metabolism*
  • Protein Kinase C-alpha
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists / pharmacology
  • Thiazoles

Substances

  • Benzopyrans
  • Caspase Inhibitors
  • Neuroprotective Agents
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists
  • Thiazoles
  • repinotan hydrochloride
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Hydrogen Peroxide
  • Prkca protein, mouse
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Mitogen-Activated Protein Kinases
  • Casp3 protein, mouse
  • Caspase 3
  • Calcium