Calmodulin Dependence of Presynaptic Metabotropic Glutamate Receptor Signaling

Abstract

Glutamatergic neurotransmission is controlled by presynaptic metabotropic glutamate receptors (mGluRs). A subdomain in the intracellular carboxyl-terminal tail of group III mGluRs binds calmodulin and heterotrimeric guanosine triphosphate-binding protein (G protein) betagamma subunits in a mutually exclusive manner. Mutations interfering with calmodulin binding and calmodulin antagonists inhibit G protein-mediated modulation of ionic currents by mGluR 7. Calmodulin antagonists also prevent inhibition of excitatory neurotransmission via presynaptic mGluRs. These results reveal a novel mechanism of presynaptic modulation in which Ca(2+)-calmodulin is required to release G protein betagamma subunits from the C-tail of group III mGluRs in order to mediate glutamatergic autoinhibition.

Physical Interaction of Calmodulin with the 5-Hydroxytryptamine2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

“…Depending on the GPCR, CaM interaction with the receptor can affect its coupling with the G protein or its phosphorylation by protein kinase C (Nakajima et al, 1999;O'Connor et al, 1999;Wang et al, 1999;Bofill-Cardona et al, 2000;Turner et al, 2004;Turner and Raymond, 2005), suggesting a possible role in receptor desensitization. CaM can also directly contribute to receptor signaling (Della Rocca et al, 1999;O'Connor et al, 1999;Nickols et al, 2004). Notably, CaM has been involved in activation of ERK1,2 signaling pathway upon stimulation of certain GPCRs (Della Rocca et al, 1999;Belcheva et al, 2001).…”

“…For example, a set of postsynaptic density 95/disc-large/zona occludens proteins bind to the SSV motif on the distal C-terminal 5-HT 2C receptor and have a key role in receptor desensitization and internalization after prolonged agonist exposure (Gavarini et al, 2006). The 5-HT 2C receptor C-terminus also interacts with calmodulin (CaM) (Becamel et al, 2002), a ubiquitous modulator of Ca 2ϩ -dependent processes that has been found to interact with many other GPCRs, including the dopamine D 2 , metabotropic glutamate mGlu5 and mGlu7, -opioid, vasopressin V2, angiotensin II AT 1A , and serotonin 5-HT 1A and 5-HT 2A receptors (Minakami et al, 1997;Nakajima et al, 1999;O'Connor et al, 1999;Thomas et al, 1999;Wang et al, 1999;Bofill-Cardona et al, 2000;Nickols et al, 2004;Turner et al, 2004;Turner and Raymond, 2005).The roles that interaction with CaM plays in receptor function are remarkably diverse. Depending on the GPCR, CaM interaction with the receptor can affect its coupling with the G protein or its phosphorylation by protein kinase C (Nakajima et al, 1999;O'Connor et al, 1999;Wang et al, 1999;Bofill-Cardona et al, 2000;Turner et al, 2004;Turner and Raymond, 2005), suggesting a possible role in receptor desensitization.…”

“…For example, a set of postsynaptic density 95/disc-large/zona occludens proteins bind to the SSV motif on the distal C-terminal 5-HT 2C receptor and have a key role in receptor desensitization and internalization after prolonged agonist exposure (Gavarini et al, 2006). The 5-HT 2C receptor C-terminus also interacts with calmodulin (CaM) (Becamel et al, 2002), a ubiquitous modulator of Ca 2ϩ -dependent processes that has been found to interact with many other GPCRs, including the dopamine D 2 , metabotropic glutamate mGlu5 and mGlu7, -opioid, vasopressin V2, angiotensin II AT 1A , and serotonin 5-HT 1A and 5-HT 2A receptors (Minakami et al, 1997;Nakajima et al, 1999;O'Connor et al, 1999;Thomas et al, 1999;Wang et al, 1999;Bofill-Cardona et al, 2000;Nickols et al, 2004;Turner et al, 2004;Turner and Raymond, 2005).…”

Increases in Intracellular Calcium Triggered by Channelrhodopsin-2 Potentiate the Response of Metabotropic Glutamate Receptor mGluR7

“…16); (gift from Dr. S. Nakanishi, University of Kyoto, Japan) and the GIRK (Kir3.1/3.2) construct (gift from Dr. Andreas Karschin, University of Würzburg, Germany) have been described previously (8). The ChR2 construct used was a C-terminally truncated version (amino acids 2-315) that lacks most of the C-terminal cytoplasmic domain (14) and contains a single point mutation (H134R), which results in larger currents but does not change ion selectivity (17).…”

“…Specifically, the cytoplasmic C-terminal tail of the predominant splice variant mGluR7a has been shown to bind proteins whose properties are directly or indirectly influenced by changes in intracellular Ca 2ϩ levels, such as calmodulin (CaM) (8), protein kinase C (9), and protein interacting with protein kinase C 1 (PICK-1) (10,11). CaM binds to mGluR7a (and other group III mGluRs) in a Ca 2ϩ -dependent manner, and CaM inhibitors have been shown to prevent presynaptic inhibition at glutamatergic autapses and to disrupt mGluR7a signaling in Xenopus oocytes (8). Moreover, inhibition of P/Q voltage-gated calcium channels by L-AP4 is blocked by BAPTA, suggesting that Ca 2ϩ is required for mGluR7-mediated presynaptic inhibition in cerebellar granule cells (6).…”