ryanodine and cyclothiazide

A major subtype of glutamate receptors, AMPA receptors (AMPARs), are generally thought to mediate excitation at mammalian central synapses via the ionotropic action of ligand-gated channel opening. It has recently emerged, however, that synaptic activation of AMPARs by glutamate released from the climbing fibre input elicits not only postsynaptic excitation but also presynaptic inhibition of GABAergic transmission onto Purkinje cells in the cerebellar cortex. Although presynaptic inhibition is critical for information processing at central synapses, the molecular mechanisms by which AMPARs take part in such actions are not known. This study therefore aimed at further examining the properties of AMPAR-mediated presynaptic inhibition at GABAergic synapses in the rat cerebellum. Our data provide evidence that the climbing fibre-induced inhibition of GABA release from interneurons depends on AMPAR-mediated activation of GTP-binding proteins coupled with down-regulation of presynaptic voltage-dependent Ca(2+) channels. A G(i/o)-protein inhibitor, N-ethylmaleimide, selectively abolished the AMPAR-mediated presynaptic inhibition at cerebellar GABAergic synapses but did not affect AMPAR-mediated excitatory actions on Purkinje cells. Furthermore, both G(i/o)-coupled receptor agonists, baclofen and DCG-IV, and the P/Q-type calcium channel blocker omega-agatoxin IVA markedly occluded the AMPAR-mediated inhibition of GABAergic transmission. Conversely, AMPAR activation inhibited action potential-triggered Ca(2+) influx into individual axonal boutons of cerebellar GABAergic interneurons. By suppressing the inhibitory inputs to Purkinje cells, the AMPAR-mediated presynaptic inhibition could thus provide a feed-forward mechanism for the information flow from the cerebellar cortex.

Topics: Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Benzothiadiazines; Benzoxazines; Calcium; Calcium Channel Blockers; Cerebellum; Chelating Agents; Colforsin; Cyclopropanes; Drug Interactions; Egtazic Acid; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; In Vitro Techniques; Morpholines; Naphthalenes; Neural Inhibition; Neurons; Piperidines; Presynaptic Terminals; Pyrazoles; Rats; Rats, Wistar; Receptors, AMPA; Ryanodine; Synapses; Triazines; Triazoles

Fura-2 fluorescent calcium imaging was applied to measure [Ca(2+)](i) in freshly dissociated horizontal cells of carp retina, and a model containing endoplasmic reticulum (ER) membrane processes and plasma membrane processes was constructed for quantitative analyses of the AMPA-triggered calcium dynamics. A transient increase followed by a sustained steady level of [Ca(2+)](i) was observed when 100 microM AMPA was applied, while the initial transient increase of [Ca(2+)](i) was suppressed by exogenously applied ryanodine. The model analyses results suggest that the AMPA-triggered calcium dynamics involves a number of cytoplasmic and endoplasmic processes that interact with each other. It also suggests that calcium store is an important part contributing to the transient calcium signal.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antihypertensive Agents; Benzothiadiazines; Calcium; Calcium Signaling; Cells, Cultured; Drug Interactions; Excitatory Amino Acid Agonists; Fura-2; Goldfish; Models, Biological; Neurons; Nonlinear Dynamics; Retina; Ryanodine