Spatial-Temporal Patterning of Metabotropic Glutamate Receptor-mediated Inositol 1,4,5-Triphosphate, Calcium, and Protein Kinase C Oscillations

The metabotropic glutamate receptors (mGluR), mGluR1a and mGluR5a, are G protein-coupled receptors that couple via G_q to the hydrolysis of phosphoinositides, the release of Ca²⁺ from intracellular stores, and the activation of protein kinase C (PKC). We show here that mGluR1/5 activation results in oscillatory G protein coupling to phospholipase C thereby stimulating oscillations in both inositol 1,4,5-triphosphate formation and intracellular Ca²⁺ concentrations. The mGluR1/5-stimulated Ca²⁺ oscillations are translated into the synchronized repetitive redistribution of PKCβII between the cytosol and plasma membrane. The frequency at which mGluR1a and mGluR5a subtypes stimulate inositol 1,4,5-triphosphate, Ca²⁺, and PKCβII oscillations is regulated by the charge of a single amino acid residue localized within their G protein-coupling domains. However, oscillatory mGluR signaling does not involve the repetitive feedback phosphorylation and desensitization of mGluR activity, since mutation of the putative PKC consensus sites within the first and second intracellular loops as well as the carboxyl-terminal tail does not prevent mGluR1a-stimulated PKCβII oscillations. Furthermore, oscillations in Ca²⁺ continued in the presence of PKC inhibitors, which blocked PKCβII redistribution from the plasma membrane back into the cytosol. We conclude that oscillatory mGluR signaling represents an intrinsic receptor/G protein coupling property that does not involve PKC feedback phosphorylation.