The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Calpha.
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.
Adayev
Tatyana
T
Department of Chemistry and the CSI/IBR Center for Developmental Neuroscience, City University of New York at the College of Staten Island, 2800 Victory Boulevard, Staten Island, NY 10314, USA.
Ray
Indrani
I
Sondhi
Rachna
R
Sobocki
Tomasz
T
Banerjee
Probal
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001578:Benzopyrans; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D002460:Cell Line; D004789:Enzyme Activation; D006861:Hydrogen Peroxide; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018696:Neuroprotective Agents; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013844:Thiazoles
D001578:Benzopyrans; D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; C111221:repinotan hydrochloride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006861:Hydrogen Peroxide; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002118:Calcium