Group I metabotropic glutamate receptors activate a calcium-sensitive transient receptor potential-like conductance in rat hippocampus.
In CA3 pyramidal neurons from organotypic slice cultures, activation of G(q)-coupled group I metabotropic glutamate receptors (mGluRs) induces a non-selective cationic conductance that enhances excitability. We have found that this response shares several properties with conductances that are mediated by the transient receptor potential (TRP) family of ion channels, including inhibition by La(3+), 2-aminoethoxydiphenylborane (2APB), cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12,330A) and a doubly rectifying current-voltage relationship. Stimulation of mGluR1 and mGluR5 converged to activate the TRP-like conductance in a synergistic manner, and activation of either subtype alone produced only a fraction of the normal response. Activation of the cationic current required elevated intracellular Ca(2+). Chelating intracellular Ca(2+) or blocking Ca(2+) entry through voltage-gated Ca(2+) channels attenuated responses to the activation of mGluRs. Conversely, raising intracellular Ca(2+) potentiated mGluR activation of the TRP-like conductance. Under control conditions, blocking G protein activation using intracellular GDPbetaS with or without N-(2, 6-dimethylphenylcarbamoylmethyl) triethylammonium chloride (QX-314) prevented mGluR-mediated activation of the TRP-like conductance. Following G protein blockade, however, the coupling between mGluRs 1 and/or 5 and the TRP-like conductance was rescued by increasing intracellular Ca(2+). This suggests that a G protein-independent signalling pathway is also activated by group I mGluRs. Such a pathway may represent an alternative transduction mechanism to maintain metabotropic responses under conditions where G proteins are functionally uncoupled from their cognate receptors.
Gee
Christine E
CE
Brain Research Institute, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Benquet
Pascal
P
Gerber
Urs
U
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*
C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D018094:Receptors, Metabotropic Glutamate; C473605:extracellular calcium cation-sensing receptor, rat; C104077:metabotropic glutamate receptor type 1; D019204:GTP-Binding Proteins; D002118:Calcium