Role of metabotropic glutamate receptors in the depression of GABA-mediated depolarization of frog primary afferent terminals.
Sucrose gap recordings from the dorsal roots of isolated, hemisected frog spinal cords were used to determine the effects of metabotropic L-glutamate receptor activation on primary afferent terminals by (+/-)-1-amino-trans-1,3-cyclopentane-dicarboxylic acid (t-ACPD). Dorsal root potentials evoked by ventral root volleys were significantly reduced by t-ACPD (30 microM), as were GABA- and muscimol-induced afferent terminal depolarizations. The effects of t-ACPD on GABA-depolarizations depended upon activation of group I metabotropic glutamate receptors, i.e. the effects were blocked by the group I/II antagonist (RS)-alpha-methyl-4-carboxyphenylglycine, but not by the group II antagonist alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine or the group III antagonist alpha-methyl-(S)-2-amino-4-phosphonobutyrate and were mimicked by the group I agonist 3,5-dihydroxyphenylglycine but were not mimicked by the group III agonist (S)-2-amino-4-phosphonobutyrate. Increasing the intracellular concentration of 3'-5'-cyclic adenosine monophosphate with 8-bromo-cAMP, forskolin, and 3-isobutyl-1-methylxanthine significantly reduced GABA depolarizations, but the protein kinase inhibitors Rp-adenosine 3,5-cyclic monophosphothioate triethylamine and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide did not alter t-ACPD's depression of GABA depolarizations. The actions of t-ACPD on GABA depolarizations were neither mimicked nor blocked by phorbol-12-myristate 13-acetate, thapsigargin, staurosporine, or arachidonic acid, presumptive indications that the effects of t-ACPD did not involve phosphoinositide hydrolysis, the release of Ca2+ from intracellular stores, or the formation of arachidonate. t-ACPD's effects on GABA depolarizations were blocked by 20 mM Mg2+, the broad spectrum L-glutamate antagonist kynurenate, and the selective N-methyl-D-aspartate antagonist D(-)-2-amino-5-phosphonovaleric acid, but not by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Low concentrations of N-methyl-D-aspartate (10 microM) mimicked the effect of t-ACPD on GABA responses. These results suggest that t-ACPD's depression of GABA depolarizations involves an indirect, three-stage mechanism that includes activation of Group I metabotropic glutamate receptors on interneurons and/or on afferent terminals, the release of L-glutamate from the latter structures, and the activation of N-methyl-D-aspartate receptors on primary afferent terminals. The depression of GABA depolarizations caused by the release of L-glutamate from afferent terminal and/or interneurons leads to a block of presynaptic inhibition (produced in the frog spinal cord by GABA) resulting in a positive feed-forward amplification of reflex transmission.
Hackman
J C
JC
Neurophysiology Laboratory, Veteran's Administration Medical Center, University of Miami School of Medicine, FL 33101, USA.
Holohean
A M
AM
Davidoff
R A
RA
D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D066298:In Vitro Techniques; D007536:Isomerism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011894:Rana pipiens; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*
D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005680:gamma-Aminobutyric Acid