Spatial-temporal patterning of metabotropic glutamate receptor-mediated inositol 1,4,5-triphosphate, calcium, and protein kinase C oscillations - Protein kinase C-dependent receptor phosphorylation is not required

The metabotropic glutamate receptors (mGluR), mGluR1a and mGluR5a, are G pr otein-coupled receptors that couple via G to the hydrolysis of phosphoinosi tides, the release of Ca2+ from intracellular stores, and the activation of protein kinase C (PKC). We show here that mGluR1/5 activation results in o scillatory G protein coupling to phospholipase C thereby stimulating oscill ations in both inositol 1,4,5-triphosphate formation and intracellular Ca2 concentrations. The mGluR1/5-stimulated Ca2+ oscillations are translated i nto the synchronized repetitive redistribution of PKC beta II between the c ytosol and plasma membrane. The frequency at which mGluR1a and mGluR5a subt ypes stimulate inositol 1,4,5-triphosphate, Ca2+, and PKC beta II oscillati ons is regulated by the charge of a single amino acid residue localized wit hin their G protein-coupling domains. However, oscillatory mGluR signaling does not involve the repetitive feedback phosphorylation and desensitizatio n of mGluR activity, since mutation of the putative PKC consensus sites wit hin the first and second intracellular loops as well as the carboxyl-termin al tail does not prevent mGluR1a-stimulated PKC beta II oscillations. Furth ermore, oscillations in Ca2+ continued in the presence of PKC inhibitors, w hich blocked PKC beta II redistribution from the plasma membrane back into the cytosol. We conclude that oscillatory mGluR signaling represents an int rinsic receptor/G protein coupling property that does not involve PKC feedb ack phosphorylation.