| 20211606 |
Gubbins EJ, Gopalakrishnan M, Li J: alpha7 nAChR-mediated activation of MAP kinase pathways in PC12 cells. Brain Res. 2010 Mar 6.
The alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) plays a fundamental role in Ca (2+)-dependent activation of signaling pathways that can modulate intracellular events involved in learning and memory. Activation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) are well documented Ca (2+) signaling events, but these have not been well characterized in response to alpha7 nAChR-selective ligands. The present study examined activation of ERK1/2 and explored pathways leading to CREB phosphorylation utilizing alpha7 nAChR-selective ligands in PC12 cells endogenously expressing alpha7 nAChRs. Robust concentration-dependent increase in ERK1/2 phosphorylation was triggered by structurally diverse alpha7 nAChR agonists such as nicotine, choline, GTS-21, SSR-180711A and PNU-282987 in the presence of the positive allosteric modulator (PAM) PNU-120596. This effect was attenuated by selective alpha7 nAChR antagonists or by chelation of extracellular Ca (2+). ERK1/2 phosphorylation was also attenuated by inhibitors of calmodulin-dependent protein kinase II (CaMKII), p38 MAP kinase and mitogen-activated protein kinase kinase1/2 (MEK1/2), indicating the involvement of these kinases upstream of ERK1/2. This was confirmed by direct measurement of p38 MAPK and MEK1/2 phosphorylation. These data suggest that alpha7 nAChR agonist-triggered Ca (2+) transient in PC12 cells induces activation of CaMKII, leading to sequential phosphorylation of p38 MAPK, MEK1/2, ERK1/2 and CREB. Such mechanisms may endow the alpha7 nAChRs with roles in modulating Ca (2+)-dependent intracellular second messenger events implicated in diverse aspects of cognition. |
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