Davies, J.A.; (2004) Cross-talk of signalling cascades in the modulation of presynaptic extracellular signal-regulated protein kinase 1 and 2 function. Doctoral thesis , University of London.

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Abstract

Activation of extracellular signal-regulated protein kinases (ERK1/2) has emerged as a key signalling event in the modulation of presynaptic plasticity by neurotrophic factors. In this study, we investigated the cross-talk between presynaptic signalling pathways activating PKA or PKC and ERK signalling, underlying the modulation of neurotransmitter release. Purified, isolated cerebrocortical nerve terminals and phosphorylation state-specific antibodies were used to carry out this research. Stimulation of PKA by cAMP, produced in response to p-adrenoreceptor activation by isoproterenol, or direct stimulation of adenylyl cyclase by forskolin, resulted in a substantial increase in ERK phosphorylation/activity. Similarly, stimulation of PKC, by PDBu, also led to stimulation of ERK phosphorylation/activity. Metabotropic glutamate receptor activation by the Group I agonist DHPG, however, led to ERK1/2 phosphorylation which showed a Ca2+ -dependency, though the role of PKC was less clearly defined. A key effector molecule for the regulation of neurotransmitter release by ERK activation is the small synaptic vesicle (SSV) protein synapsin I, which, through alteration in its phosphorylation-state, modulates SSV-actin cytoskeleton interactions and thereby controls the distribution of SSVs between release pools. Accordingly, with both PKA and PKC activation of ERKs, the downstream stimulation of synapsin phosphorylation at specific ERK-dependent sites was also detected. These results suggest that, together with the established roles of PKA and PKC acting on ion- channel targets to modulate of presynaptic excitability and/or voltage-dependent Ca-entry, downstream of these loci, the two kinase cascades may converge at the level of SSV mobilization to regulate the efficacy of glutamate release from cerebrocortical nerve terminals.

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