Diversity of calcium signaling by metabotropic glutamate receptors

During prolonged application of glutamate (20 min), patterns of increase in intracellular Ca2+ concentration ([Ca2+](i)) were studied in HEK-293 cells expressing metabotropic glutamate receptor, mGluR1 alpha or mGluR5a, Stimulation of mGluR1 alpha induced an increase in [Ca2+](i), that consisted of an initial transient peak with a subsequent steady plateau or an oscillatory increase in [Ca2+](i). The transient phase was largely attributed to Ca2+ mobilization from the intracellular Ca2+ stores, but the sustained phase was solely due to Ca2+ influx through the mGluR1 alpha receptor-operated Ca2+ channel. Prolonged stimulation of mGluR5a continuously induced [Ca2+](i) oscillations through mobilization of Ca2+ from the intracellular Ca2+ stores, Studies on mutant receptors of mGluR1 alpha and mGluR5a revealed that the coupling mechanism in the sustained phase of Ca2+ response is determined by oscillatory/non-oscillatory patterns of the initial Ca2+ response but not by the receptor identity. In mGluR1 alpha-expressing cells, activation of protein kinase C selectively desensitized the pathway for intracellular Ca2+ mobilization, but the mGluR1 alpha-operated Ca2+ channel remained active. In mGluR5a-expressing cells, phosphorylation of mGluR5a by protein kinase C, which accounts for the mechanism of mGluR5a controlled [Ca2+](i) oscillations, might prevent desensitization and result in constant oscillatory mobilization of Ca2+ from intracellular Ca2+ stores. Our results provide a novel concept in which oscillatory/non-oscillatory mobilizations of Ca2+ induce different coupling mechanisms during prolonged stimulation of mGluRs.