Activation of ATP-sensitive K+ (KATP) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release

AUTOR(ES)

Avshalumov, Marat V.

FONTE

National Academy of Sciences

RESUMO

In many cells, ATP-sensitive K+ channels (KATP channels) couple metabolic state to excitability. In pancreatic beta cells, for example, this coupling regulates insulin release. Although KATP channels are abundantly expressed in the brain, their physiological role and the factors that regulate them are poorly understood. One potential regulator is H2O2. We reported previously that dopamine (DA) release in the striatum is modulated by endogenous H2O2, generated downstream from glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor activation. Here we investigated whether H2O2-sensitive KATP channels contribute to DA-release modulation by glutamate and γ-aminobutyric acid (GABA). This question is important because DA–glutamate interactions underlie brain functions, including motor control and cognition. Synaptic DA release was evoked by using local electrical stimulation in slices of guinea pig striatum and monitored in real time with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. The KATP-channel antagonist glibenclamide abolished the H2O2-dependent increase in DA release usually seen with AMPA-receptor blockade by GYKI-52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the decrease in DA release seen with GABA-type-A-receptor blockade by picrotoxin. In contrast, 5-hydroxydecanoate, a mitochondrial KATP-channel blocker, was ineffective, as were sulpiride, a D2-receptor antagonist, and tertiapin, a G protein-coupled K+-channel inhibitor. Diazoxide, a sulfonylurea receptor 1 (SUR1)selective KATP-channel opener, prevented DA modulation by H2O2, glutamate, and GABA, whereas cromakalim, a SUR2-selective opener, did not. Thus, endogenous H2O2 activates SUR1-containing KATP channels in the plasma membrane to inhibit DA release. These data not only demonstrate that KATP channels can modulate CNS transmitter release in response to fast-synaptic transmission but also introduce H2O2 as a KATP-channel regulator.

Documentos Relacionados

• ATP-sensitive K+ channels in rat pancreatic beta-cells: modulation by ATP and Mg2+ ions.
• ATP-Sensitive K+ Channels Regulate the Concentrative Adenosine Transporter CNT2 following Activation by A1 Adenosine Receptors
• ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle.
• Effects of intracellular pH on ATP-sensitive K+ channels in mouse pancreatic beta-cells.
• ATP-sensitive K+ channels are functional in expiratory neurones of normoxic cats.