L-type calcium channel ligands block nicotine-induced signaling to CREB by inhibiting nicotinic receptors

Neuropharmacology
Damian G WheelerRichard W Tsien

Abstract

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 s...Continue Reading

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Citations

Apr 29, 2008·Learning & Memory·Perrine BusquetNicolas Singewald
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Thomas P GiordanoAnjali M Rajadhyaksha
Nov 8, 2011·Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association·Xu JiKazuyoshi Kurahashi
Apr 5, 2014·Neuron·Brett A Simms, Gerald W Zamponi
Sep 27, 2008·Brain Research·Sandra RafalzikRüdiger Gerstberger
Feb 27, 2009·American Journal of Physiology. Cell Physiology·Mariko Sekiguchi-TonosakiJun Kosaka
Oct 21, 2006·Biochemical Society Transactions·J StriessnigN Singewald

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