Atypical signaling of metabotropic glutamate receptor 1 in human melanoma cells.
The metabotropic glutamate 1 (mGlu1) receptor has emerged as a novel target for the treatment of metastatic melanoma and various other cancers. Our laboratory has demonstrated that a selective, non-competitive mGlu1 receptor antagonist slows human melanoma growth in vitro and in vivo. In this study, we sought to determine if the activation of a canonical G protein-dependent signal transduction cascade, which is often used as an output of mGlu1 receptor activity in neuronal cells, correlated with mGlu1 receptor-mediated melanoma cell viability. Glutamate, the endogenous ligand of mGlu1 receptors, significantly increased melanoma cell viability, but did not stimulate phosphoinositide (PI) hydrolysis in several human melanoma cell lines. In contrast, melanoma cell viability was not increased by quisqualate, a highly potent mGlu1 receptor agonist, or DHPG, a selective group I mGlu receptor agonist. Similarly to glutamate, quisqualate also failed to stimulate PI hydrolysis in mGlu1 receptor-expressing melanoma cells. These results suggest that the canonical G protein-dependent signal transduction cascade is not coupled to mGlu1 receptors in all human melanoma cells. On the other hand, dynamin inhibition selectively decreased viability of mGlu1 receptor-expressing melanoma cells, suggesting that a mechanism requiring internalization may control melanoma cell viability. Taken together, these data demonstrate that the approaches commonly used to study mGlu1 receptor function and signaling in other systems may be inappropriate for studying mGlu1 receptor-mediated melanoma cell viability.
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: gelbtara@gmail.com.
Tara
T
Gelb
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: pshenics@gmail.com.
Sergey
S
Pshenichkin
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: hannah.a.hathaway@gmail.com.
Hannah A
HA
Hathaway
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: ewagrajkowska@gmail.com.
Ewa
E
Grajkowska
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: ccb23@georgetown.edu.
Carrie Bowman
CB
Dalley
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: bwolfe01@georgetown.edu.
Barry B
BB
Wolfe
Department of Pharmacology and Physiology, Georgetown University, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA. Electronic address: wroblewj@georgetown.edu.
Jarda T
JT
Wroblewski
D000255:Adenosine Triphosphate / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction
C487266:9alpha,10beta-dihydroxy-2beta,4beta-peroxy-1alpha,5beta,7alphaH-guaiane; D018094:Receptors, Metabotropic Glutamate; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C104077:metabotropic glutamate receptor type 1; D015759:Ionomycin; D000255:Adenosine Triphosphate; D016318:Quisqualic Acid
(S)-3,5-DHPG (PubChem CID: 443586); Adenosine triphosphate (PubChem CID: 5957); CPCCOEt (PubChem CID: 6278000); Dimethyl sulfoxide (PubChem CID: 679); Dynasore (PubChem CID: 5717066); Forskolin (PubChem CID: 47936); Glutamate; Ionomycin calcium salt (PubChem CID: 6446270); Isoproterenol (PubChem CID: 3779); JNJ16259685 (PubChem CID: 11313361); Melanoma; Metabotropic glutamate receptor 1; Phosphoinositide hydrolysis; Quisqualate; l-Glutamic acid (PubChem CID: 33032); l-Quisqualic acid (PubChem CID: 6603978)