Diversity of Calcium Signaling by Metabotropic Glutamate Receptors

During prolonged application of glutamate (20 min), patterns of increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) were studied in HEK-293 cells expressing metabotropic glutamate receptor, mGluR1α or mGluR5a. Stimulation of mGluR1α induced an increase in [Ca 2+ ] 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 Ca 2+ mobilization from the intracellular Ca 2+ stores, but the sustained phase was solely due to Ca 2+ influx through the mGluR1α receptor-operated Ca 2+ channel. Prolonged stimulation of mGluR5a continuously induced [Ca2+] i oscillations through mobilization of Ca 2+ from the intracellular Ca 2+ stores. Studies on mutant receptors of mGluR1α and mGluR5a revealed that the coupling mechanism in the sustained phase of Ca 2+ response is determined by oscillatory/non-oscillatory patterns of the initial Ca 2+ response but not by the receptor identity. In mGluR1α-expressing cells, activation of protein kinase C selectively desensitized the pathway for intracellular Ca 2+ mobilization, but the mGluR1α-operated Ca 2+ 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 Ca 2+ from intracellular Ca 2+ stores. Our results provide a novel concept in which oscillatory/non-oscillatory mobilizations of Ca 2+ induce different coupling mechanisms during prolonged stimulation of mGluRs.