In transfected cells and non-neuronal tissues many G-protein-coupled receptors activate p44/42 MAP kinase (ERK), a kinase involved in both hippocampal synaptic plasticity and learning and memory. However, it is not clear to what degree these receptors couple to ERK in brain. G s -coupled ␤-adrenergic receptor activation of ERK in neurons is critical in the regulation of synaptic plasticity in area CA1 of the hippocampus. In addition, ␣ 1 -and ␣ 2 -adrenergic receptors, present in CA1, could potentially activate ERK. We find that, like the ␤-adrenergic receptor, the G q -coupled ␣ 1 AR activates ERK in adult mouse CA1. However, activation of the G i/o -coupled ␣ 2 AR does not activate ERK, nor does activation of a homologous G i/o -coupled receptor enriched in adult mouse CA1, the 5HT 1A receptor. In contrast, the nonhomologous G i/o -coupled ␥-aminobutyric acid type B receptor does activate ERK in adult mouse CA1. Surprisingly, activation of ␣ 2 ARs in CA1 from immature animals where basal phospho-ERK is low induces ERK phosphorylation. These data suggest that although most G-protein-coupled receptor subtypes activate ERK in non-neuronal cells, the coupling of G i/o to ERK is tightly regulated in brain.Protein phosphorylation plays a critical role in synaptic plasticity and learning and memory in vertebrates. A growing body of evidence suggests that the p44/42 MAP 1 kinase (ERK) cascade in particular plays important roles in the modulation of long-term potentiation in area CA1 of the hippocampus and is required for several forms of learning and memory (1). Given the roles of this kinase cascade in transcriptionally regulated processes, initial studies focused on its roles in long term forms of both long-term potentiation of synaptic transmission in the hippocampus and hippocampus-dependent long term memory formation (2-7). More recent studies, however, implicate a role for this kinase in more moment-to-moment cellular excitability (8, 9). Thus, the ERK signaling cascade regulates several aspects of synaptic transmission.Because of the multiple roles ERK may play in neuronal function it is critical to understand how the activation of this kinase is regulated in neurons. A number of receptor signaling pathways critical to synaptic plasticity recruit ERK activation in the hippocampus. As in many cell types, ligands for receptor tyrosine kinases, such as neurotrophins, recruit ERK activation in neurons, as does N-methyl D-aspartate receptor activation (10, 11). In addition, neuromodulators such as norepinephrine (NE) that activate GPCRs play critical roles in learning and memory and synaptic plasticity, at least in part through the regulation of ERK activity. For example, the activation of one adrenergic receptor, the G s -coupled ␤-adrenergic receptor, results in increased ERK activity and facilitates ERK-dependent forms of long-term potentiation in CA1 (8, 9, 12, 13). However, this receptor is not likely to be activated alone in vivo but rather in concert with other NE receptors, including the G qcoupled ␣ 1 -adre...