Phosphorylation of neuronal proteins by kinases has been proposed to play a key role in the regulation and expression of the actions of many neurotransmitters. However, to date few studies on kinases have actually tested what effect they have on neuronal physiology. The studies proposed here will focus primarily on the electrophsiological consequences of protein kinase A and C activation in the hippocampus. Previous results from this laboratory indicate that activation of protein kinase A, by application of cAMP and its analogs results in a blockage of a calcium-activated potassium current (IAHP). Preliminary evidence suggests that activation of protein kinase C, (PKC) using phorbol esters (PEs) has four different effects on hippocampal pyramidal cells (HPCs): 1) blockade of IAHP; 2) blockade of voltage-dependent chloride current (IC1(V)); 3) enhancement of excitatory synaptic transmission; and 4) blockade of responses evoked by GABAB receptor activation. Three projects will be carried out in this study. First, the effects of PEs on synaptic transmission will be determined using conventional extra- and intracellular recording techniques. The enhancement of excitatory transmission by PKC activation and its possible involvement in long term potentiation will be studied. Second, the mechanisms of action of PEs and cAMP on IAHP and IC1(V) will be determined using a single-electrode voltage clamp of intact HPCs from slices and also using whole-cell recording and patch clamp recording from primary cell cultures. Third, the mechanism of action of PEs on responses evoked by GABAB receptor activation will be examined. Neurotransmitters which have been proposed to exert their actions through PKC activation will be tested for their ability to mimic each of the actions of PEs. Calcium loading of cells as well as application of 1-oleoyl- glycerol will be used as alternate methods (to PEs) to activate PKG. The proposed studies will greatly increase our understanding of the role that kinases play in CNS neurons by actually testing the effects of kinase activation on the physiology of HPCs. These studies will also provide information on ways in which the activity of neurons can be modulated. Finally, these studies should contribute to our knowledge of psychiatric disorders since many of the neurotransmitters implicated in these disorders act via protein kinases.
| Ullman, Julie C; Yang, Jing; Sullivan, Michael et al. (2018) A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry. Nat Commun 9:330 |
| Nguyen, Quynh-Anh; Nicoll, Roger A (2018) The GABAA Receptor ? Subunit Is Required for Inhibitory Transmission. Neuron 98:718-725.e3 |
| Horn, Meryl E; Nicoll, Roger A (2018) Somatostatin and parvalbumin inhibitory synapses onto hippocampal pyramidal neurons are regulated by distinct mechanisms. Proc Natl Acad Sci U S A 115:589-594 |
| Won, Sehoon; Levy, Jon M; Nicoll, Roger A et al. (2017) MAGUKs: multifaceted synaptic organizers. Curr Opin Neurobiol 43:94-101 |
| Won, Sehoon; Incontro, Salvatore; Nicoll, Roger A et al. (2016) PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61. Proc Natl Acad Sci U S A 113:E4736-44 |
| Chen, Xiaobing; Levy, Jonathan M; Hou, Austin et al. (2015) PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. Proc Natl Acad Sci U S A 112:E6983-92 |
| Herring, Bruce E; Silm, Katlin; Edwards, Robert H et al. (2015) Is Aspartate an Excitatory Neurotransmitter? J Neurosci 35:10168-71 |
| Lovero, Kathryn L; Fukata, Yuko; Granger, Adam J et al. (2015) The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proc Natl Acad Sci U S A 112:E4129-37 |
| Bemben, Michael A; Nguyen, Quynh-Anh; Wang, Tongguang et al. (2015) Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses. Proc Natl Acad Sci U S A 112:2551-6 |
| Levy, Jonathan M; Chen, Xiaobing; Reese, Thomas S et al. (2015) Synaptic Consolidation Normalizes AMPAR Quantal Size following MAGUK Loss. Neuron 87:534-48 |
Showing the most recent 10 out of 65 publications
