Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons.
Pituitary adenylate cyclase activating polypeptide has been shown to reduce apoptosis in neonatal cerebellar and olfactory receptor neurons, however the underlying mechanisms have not been elucidated. In addition, the neuroprotective effects of pituitary adenylate cyclase activating polypeptide have not been examined in adult tissues. To study the effects of pituitary adenylate cyclase activating polypeptide on neurons in apoptosis, we measured caspase activation in adult olfactory receptor neurons in vitro. Interestingly, we found that the protective effects of pituitary adenylate cyclase activating polypeptide were related to the absence of a 4-aminopyridine (IC50=144 microM) sensitive rapidly inactivating potassium current often referred to as A-type current. In the presence of 40 nM pituitary adenylate cyclase activating polypeptide 38, both A-type current and activated caspases were significantly reduced. A-type current reduction by pituitary adenylate cyclase activating polypeptide was blocked by inhibiting the phospholipase C pathway, but not the adenylyl cyclase pathway. Our observation that 5 mM 4-aminopyridine mimicked the caspase inhibiting effects of pituitary adenylate cyclase activating polypeptide indicates that A-type current is involved in apoptosis. This work contributes to our growing understanding that potassium currents are involved with the activation of caspases to affect the balance between cell life and death.
Han
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Interdepartmental Neuroscience Program, University of Utah, Salt Lake City, UT 84108, USA.
Lucero
M T
MT
D015761:4-Aminopyridine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D015201:Meta-Analysis as Topic; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000494:pharmacology; D009831:Olfactory Mucosa / Q000166:cytology*; D018034:Olfactory Receptor Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011419:Propidium / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
C495402:Adcyap1 protein, mouse; D004791:Enzyme Inhibitors; D004963:Estrenes; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C017759:9-(tetrahydro-2-furyl)-adenine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011419:Propidium; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D015761:4-Aminopyridine; D020169:Caspases; D000225:Adenine; D013755:Tetradecanoylphorbol Acetate