L-type calcium channel ligands block nicotine-induced signaling to CREB by inhibiting nicotinic receptors.
Nicotinic acetylcholine receptors (nAChRs) are inhibited by several drugs that are commonly thought to be specific for L-type calcium channels (LTCCs). In neurons, LTCCs are activated by nicotine-induced depolarization to engage downstream signaling events; however, the role of LTCC drug interactions with nAChRs in signaling has not been examined in detail. We investigated the effects of LTCC ligands on nAChR currents and downstream signaling in rat superior cervical ganglion (SCG) neurons. We found that 10microM nicotine and 40mM K(+) both reversibly depolarize SCG neurons to -20mV, sufficient to activate LTCCs and downstream signaling, including induction of nuclear phospho-CREB (pCREB); this induction was blocked by LTCC antagonists. Interestingly, the effects of LTCC antagonists on nicotine-induced signaling to CREB are not mediated by their actions on LTCCs, but rather via inhibition of nAChRs, which prevents nicotine-induced depolarization. We show that this effect is sufficient to block pCREB induction in neurons expressing an antagonist-insensitive LTCC. Taken together, our data show that, at concentrations typically used to block LTCCs, these antagonists inhibit nAChR currents and downstream signaling. These findings serve as a caution in attributing a role for LTCCs when using these drugs experimentally or therapeutically.
Wheeler
Damian G
DG
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
Barrett
Curtis F
CF
Tsien
Richard W
RW
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000503:physiopathology; D003627:Data Interpretation, Statistical; D004095:Dihydropyridines / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D007150:Immunohistochemistry; D008024:Ligands; D016296:Mutagenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D004095:Dihydropyridines; D008024:Ligands; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic