Nicotine activates the extracellular signal-regulated kinase 1/2 via the alpha 7 nicotinic acetylcholine receptor and protein kinase A, in SH-SY5Y cells and hippocampal neurones

F A Dajas-Bailador, L Soliakov, S Wonnacott

Research output: Contribution to journalArticlepeer-review

162 Citations (Scopus)

Abstract

Neuronal nicotinic acetylcholine receptors (nAChR) can modulate many cellular mechanisms, such as cell survival and memory processing, which are also influenced by the serine/ threonine protein kinases ERK1/2. In SH-SY5Y cells and hippocampal neurones, nicotine (100 mum) increased the activity of ERK1/2. This effect was Ca2+ dependent, and prevented by the alpha7 nAChR antagonist alpha-bungarotoxin (alpha-Bgt) and an inhibitor (PD98059) of the upstream kinase MEK. To determine the intervening steps linking Ca2+ entry to MEK-ERK1/2 activation, inhibitors of Ca2+-dependent kinases were deployed. In SH-SY5Y cells, selective blockers for PKC (Ro 31-8220), CaM kinase II (KN-62) or P13 kinase (LY 294002) failed to inhibit the nicotine-evoked increase in ERK1/2 activity. In contrast, two structurally different inhibitors of PKA (KT 5720 and H-89) completely prevented the nicotine-dependent increase in ERK1/2 activity. Inhibition of the nicotine-evoked increase in ERK1/2 activity by H-89 was also observed in hippocampal cultures. Down stream of PKA, the activity of B-Raf was significantly decreased by nicotine in SH-SY5Y cells, as determined by direct measurement of MEK1 phosphorylation or in vitro kinase assays, whereas the modulation of MEK1 phosphorylation by Raf-1 tended to increase. Thus, this study provides evidence for a novel signalling route coupling the stimulation of alpha7 nAChR to the activation of ERK1/2, in a Ca2+ and PKA dependent manner.
Original languageEnglish
Pages (from-to)520-530
Number of pages11
JournalJournal of Neurochemistry
Volume80
Issue number3
DOIs
Publication statusPublished - Feb 2002

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