The weaver mutation reverses the function of dopamine and GABA in mouse dopaminergic neurons.
In the present study, we characterized the intrinsic electrophysiological properties and the membrane currents activated by dopamine (DA) D(2) and GABA(B) receptors in midbrain dopaminergic neurons, maintained in vitro in a slice preparation, from wild-type and homozygous weaver (wv/wv) mice. By using patch-clamp techniques, we found that membrane potential, apparent input resistance, and spontaneous firing of wv/wv dopaminergic neurons were similar to those of dopamine-containing cells recorded from nonaffected (+/+) animals. More interestingly, the wv/wv neurons were excited rather than inhibited by dopamine and the GABA(B) agonist baclofen. This neurotransmitter-mediated excitation was attributable to the activation of a G-protein-gated inward current that reversed polarity at a membrane potential of approximately -30 mV. We suggest that the altered behavior of the receptor-operated wv G-protein-gated inwardly rectifying K(+) channel 2 (GIRK2) might be related to the selective degeneration of the dopaminergic neurons. In addition, the wv GIRK2 would not only suppress the autoreceptor-mediated feedback inhibition of DA release but could also establish a feedforward mechanism of DA release in the terminal fields.
Guatteo
E
E
Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome, Italy.
Fusco
F R
FR
Giacomini
P
P
Bernardi
G
G
Mercuri
N B
NB
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000033:anatomy & histology / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017448:Receptors, Dopamine D2; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D019204:GTP-Binding Proteins; D001418:Baclofen; D004298:Dopamine