PROTEIN-KINASE-C MODULATES GLUTAMATE RECEPTOR INHIBITION OF CA2+ CHANNELS AND SYNAPTIC TRANSMISSION

FAST synaptic transmission in the central nervous system can be modulated by neurotransmitters and second-messenger pathways. For example, transmission at glutamatergic synapses can be depressed by the metabotropic glutamate receptor1,2, providing autoreceptor-mediated negative feedback. Metabotropic glutamate receptor inhibition of Ca2+ channels may contribute to this pathway3-6. In contrast, stimulation of protein kinase C can enhance excitatory synaptic transmission7, whereas both depression and enhancement of Ca2+ current have been reported8. Here we show that in hippocampal CA3 and cortical pyramidal neurons, activation of protein kinase C enhances current through N-type Ca2+ channels and, in addition, dramatically reduces G protein-dependent inhibition of these same channels by the metabotropic glutamate receptor. In parallel experiments on fast excitatory transmission at corticostriatal synapses, kinase C activators were similarly found to reduce the inhibitory effect produced by stimulation of the metabotropic glutamate receptor. The results show that second-to-second control of Ca2+ channels by the metabotropic glutamate receptor can itself be modulated on a slower timescale by protein kinase C. These mechanisms may be used in the control of fast excitatory synaptic transmission.