Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation.
Metabotropic receptors coupled to Gq/G11 family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of Gq/G11 family G proteins in the regulation of neuronal excitability in mice that selectively lack the alpha-subunits of Gq and G11, G alpha q and G alpha 11, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired. We found that endocannabinoid levels were reduced under both basal and excitotoxic conditions and that increased susceptibility to kainic acid could be normalized by the enhancement of endocannabinoid levels with an endocannabinoid reuptake inhibitor, while the competitive cannabinoid type 1 receptor antagonist SR141716A did not cause further aggravation. These findings indicate that Gq/G11 family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of Gq/G11 contributes to this phenotype.
Wettschureck
Nina
N
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
van der Stelt
Mario
M
Tsubokawa
Hiroshi
H
Krestel
Heinz
H
Moers
Alexandra
A
Petrosino
Stefania
S
Schütz
Günther
G
Di Marzo
Vincenzo
V
Offermanns
Stefan
S
D000367:Age Factors; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis*; D063388:Endocannabinoids; D004827:Epilepsy / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists; D021122:Protein Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007608:Kainic Acid