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The Journal of Neuroscience, May 15, 2003, 23(10):4066-4071

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Evidence for Protein Tyrosine Phosphatase, Tyrosine Kinase, and G-Protein Regulation of the Parallel Fiber Metabotropic Slow EPSC of Rat Cerebellar Purkinje Neurons

Marco Canepari and David Ogden

National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

The slow EPSP (sEPSP) or slow EPSC (sEPSC) at parallel fiber to Purkinje neuron synapses is attributable to a nonselective cation channel coupled to activation of metabotropic type 1 glutamate receptors (mGluR1s). Photorelease of L-glutamate in 1 msec from 4-methoxy-7-nitroindolinyl-or 7-nitroindolinyl-caged glutamate in cerebellar slices was used to isolate and study postsynaptic mechanisms coupling mGluR1 to the cation channel. L-Glutamate immediately activated a glutamate transporter current, followed by the slow mGluR1-activated conductance. Inhibitors of kinases, phosphatases, and G-proteins were tested on the peak glutamate-evoked currents. No effects of the inhibitors were seen on the initial glutamate transporter currents. In contrast, the later mGluR1 currents were either unaffected or enhanced by the protein tyrosine kinase (PTK) inhibitors PP1, K252a, and staurosporine were diminished or blocked by phosphatase inhibitors but were unaffected by inhibitors of serine–threonine kinases PKA, PKC, or PKG. The selective src-PTK inhibitor PP1 (10 µM intracellularly) potentiated submaximal mGluR1 currents evoked by low L-glutamate concentrations but had no effect on maximal responses (80 or 160 µM L-glutamate). L-Glutamate-evoked mGluR1 currents and parallel fiber sEPSCs were reversibly and completely inhibited by protein tyrosine phosphatase (PTP) inhibitor bpV(phen) (50–200 µM) and by nonselective phosphatase inhibitor orthovanadate (0.5 or 1 mM). mGluR1 currents were completely inhibited by GDPS applied intracellularly (5 mM). The results confirm a role for a GTPase postsynaptically, show that tyrosine phosphorylation inhibits mGluR1 coupling to the channel, and show that PTPs increase activation by tyrosine dephosphorylation most likely upstream of the sEPSP cation channel.

Key words: cerebellum; Purkinje neuron; parallel fiber; slow EPSP; metabotropic glutamate receptor; tyrosine phosphorylation

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Received Sep. 6, 2002; revised Feb. 6, 2003; accepted Feb. 6, 2003.

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