Multiple calcium channels and kinases mediate alpha7 nicotinic receptor neuroprotection in PC12 cells.
alpha7 Nicotinic receptors are calcium permeant and provide neuroprotection against many insults. We investigated the roles of intracellular calcium ions and downstream calcium channels in this protection. The alpha7 agonist GTS-21 prevented pheochromocytoma cell death induced by nerve growth factor + serum deprivation over a 3-day interval. This effect was blocked by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in a manner that did not appear to involve changes in receptor density. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid blocked GTS-21-induced protein kinase C activation, a necessary process for protection. The insositol triphosphate calcium-channel blocker xestospongin C and the phospholipases C inhibitor U-73122 blocked protection, ryanodine partially attenuated protection, but the L-type channel antagonist nifedipine had no effect. ERK1/2 but not JNK and p38 were activated by GTS-21, and the ERK phosphorylation inhibitors PD98059 and U0126 blocked protection.
Ren
Ke
K
Department of Pharmaceutics, University of Florida, Gainesville, Florida 32610, USA.
Puig
Viviana
V
Papke
Roger L
RL
Itoh
Yoshihito
Y
Hughes
Jeffrey A
JA
Meyer
Edwin M
EM
D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D019610:Cytoprotection; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D015220:Calcium Channels; D002614:Chelating Agents; C579165:Chrna7 protein, rat; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004533:Egtazic Acid; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D020932:Nerve Growth Factor; D010770:Phosphotransferases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid