also be activated by calcium influx through L-type calcium channels or NMDA receptors through stimulation of Ras protein-specific guanine-nucleotide releasing factor (Ras-GRF1), a Ca2+-activated guanine nucleotide exchange factor expressed in neurons of the central nervous system.11 Ca2+ influx can be enhanced by Gs-coupled neurotransmitter receptors such as the dopamine D1 receptor, which increase protein kinase A (PKA)-mediated phosphorylation and ion channel function.12 Activated Ras in turn activates Raf, which phosphorylates and activates MAPK/ERK kinases (MEK1 and MEK2) that phosphorylate and activate the ERKs.13 ERK activity is also modulated by other signal transduction molecules, such as PKA and dopamine- and cAMP-regulated phospho-protein of 32kDa (DARPP-32, also called PPP1R1B; protein phosphatase 1, regulatory [inhibitor] subunit 1B),12 (Fig. 1) as discussed later. As ERK activity is regulated by dopamine and glutamate receptor stimulation and incorporates signals from many second messenger pathways, ERKs may function as coincidence detectors that combine rewards and contextual information in learning processes.8 Thus, ERK activity has been proposed to play integrative roles in the development of drug addictions.
