The discovery of an unsuspected number of protein-protein interactions during the past 15 years was an eye opener for the unanticipated detailed spatial and functional organization of proteins inside cells. Colocalization of protein kinases and phosphatases with their regulators and substrates is of special interest because it is critical for swift, effective, and specific signaling (189). At the plasma membrane a number of extracellular signals are relayed with high selectivity to specific intracellular signaling pathways. Synapses are rather small subcellular compartments that fulfill multiple functions: signal transmission between neurons, processing of neuronal signals, and storage of information. Targeting mechanisms for kinases and phosphatases are thus particularly important at synapses to ensure spatial and temporal fidelity of signal transduction. Such targeting is not limited to kinases but often includes upstream regulators and downstream effectors of kinases. For instance, PKA forms a signaling complex with the postsynaptic L-type Ca2+ channel Cav1.2 that contains all elements of the classic ?-adrenergic - PKA signaling cascade including the ?2 adrenergic receptor, the trimeric G protein Gs, and adenylyl cyclase (55, 93). Upon activation of the ?2 adrenergic receptor and the ensuing cAMP production, PKA phosphorylates Cav1.2 to increase its Ca2+ channel activity. Despite involving the diffusible second messenger cAMP, signaling from the ?2 adrenergic receptor via PKA to Cav1.2 is spatially highly restricted fostered by the formation of a supramolecular signaling complex (55). This chapter describes the molecular basis and functional relevance of postsynaptic kinase and phosphatase anchoring at glutamatergic synapses. Glutamate is the main excitatory neurotransmitter in the brain. Most synaptic events are mediated by AMPA-type glutamate receptors. A temporary increase in transmission frequency leads to activation of NMDA-type glutamate receptors. The resulting Ca2+ influx through NMDA receptors causes long-term-depression (LTD) at more modest frequencies (1-3 Hz) and long-term potentiation (LTP) at higher frequencies. AMPA and NMDA receptors are described in Chapters by Mayer, Esteban, Yuan et al., Wenthold et al., and Choquet and Triller, this volume and LTP in Chapter by Lisman and Hell, this volume. Detailed information is available for postsynaptic localization of the protein kinases CaMKII, PKA, PKC, Pyk2, Src, and Fyn, and of the phosphatases PP1, PP2A, and PP2B. We will also describe upstream regulators and downstream effectors and substrates of these kinases and phosphatases in regards to their spatial co-distribution.
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