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 µm) increased the activity of ERK1/2. This effect was Ca²⁺ dependent, and prevented by the α7 nAChR antagonist α‐bungarotoxin (α‐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 PI3 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 α7 nAChR to the activation of ERK1/2, in a Ca²⁺ and PKA dependent manner.