Different Conformations Prefer Distinct Signaling Pathways

Abstract

The metabotropic glutamate receptor 1α (mGluR1α), a homodimeric G protein-coupled receptor critically involved in some forms of synaptic plasticity, can stimulate an increase in intracellular calcium concentration ([Ca 2+ ] i ) through Gq or an increase in intracellular adenosine 3′,5′-monophosphate (cAMP) concentration ([cAMP] i ) through Gs. Each mGluR1α subunit contains an extracellular "Venus flytrap" module; glutamate binding stabilizes an active conformation in which the Venus flytrap of one subunit closes while the other stays open (closed-open/active, CO/A). In the presence of Gd 3+ , which binds to the interface between subunits, glutamate binds to both subunits, leading to a closed-closed/active (CC/A) conformation. Tateyama and Kubo used fluorescent indicators to simultaneously measure [Ca 2+ ] i and [cAMP] i in CHO (Chinese hamster ovary) cells expressing mGluR1α and explored the relation between the two active conformations and coupling to the two signaling pathways. Whereas glutamate stimulated increases in both [Ca 2+ ] i and [cAMP] i , Gd 3+ stimulated an increase only in [Ca 2+ ] i . Moreover, Gd 3+ decreased mGluR1α activation of Gs (the ability to increase [cAMP] i ) in response to glutamate but did not affect coupling to Gq (the ability to increase [Ca 2+ ] i ). Thus, the authors conclude that, rather than acting as a simple "on/off switch," the different active conformations of mGluR1α preferentially interact with distinct G proteins and thereby activate distinct intracellular signaling pathways. M. Tateyama, Y. Kubo, Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1α. Proc. Natl. Acad. Sci. U.S.A. 103 , 1124-1128 (2006). [Abstract] [Full Text]