title: Extracellular proton modulates GABAergic synaptic transmission in rat hippocampal CA3 neurons.
abstract: Acidification, which occurs in some pathological conditions, such as ischemia and hypoxia often induces neurotoxicity. The activation of acid-sensing ion channels (ASICs), which are highly permeable to calcium, has been considered the main target responsible for calcium overload in ischemic/hypoxic brain. However, the influence of extracellular proton on GABAergic synaptic transmission is not well understood. In the rat (aged 6-12 postnatal days) hippocampal CA3 neurons dissociated with an enzyme-free, mechanical method, we show that raising the extracellular pH (to 8.5) or lowering it (to 6.0) significantly increased or decreased, respectively, the frequency and the amplitude of spontaneous inhibitory postsynaptic currents mediated by gamma-aminobutyric acid A (GABA(A)) receptors. Interestingly, these modifications were not altered by amiloride (100 microM, an antagonist for ASICs), tetrodotoxin (0.5 microM, a sodium channel blocker), cadmium (100 microM, a nonselective blocker for voltage-gated calcium channels), or a medium containing low calcium (0.5 mM). Significantly, changes in extracellular pH biphasically altered the peak amplitude of the currents elicited by exogenous GABA in CA3 neurons dissociated with enzyme. Raising the extracellular pH (to 8.5) or lowering (to 6.5) shifted the concentration-response curves of GABA to the left or right, respectively, without altering the maximal responses. These data suggest that proton alters the apparent affinity of GABA receptors for agonist. Thus, extracellular proton modifies GABAergic synaptic transmission both presynaptically and postsynaptically, and this could be independent of ASICs and voltage-gated calcium channels. Our finding may constitute a new mechanism underlying acidification-induced neurotoxicity.
authors.affiliation: Department of Anesthesiology, Pharmacology and Physiology, New Jersey Medical School, UMDNJ, Rutgers-UMDNJ Integrative Neuroscience Program, 185 South Orange Avenue, Newark, NJ 07103-2714, USA.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Zhou
authors.forename: Cheng
authors.initials: C
authors.lastname: Xiao
authors.forename: Chunyu
authors.initials: C
authors.lastname: Deng
authors.forename: Jiang
authors.initials: J
authors.lastname: Hong Ye
mesh_terms: D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D011522:Protons; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D062565:Acid Sensing Ion Channels; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011522:Protons; D011963:Receptors, GABA-A; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid; D000584:Amiloride