INGEBI   02650
INSTITUTO DE INVESTIGACIONES EN INGENIERIA GENETICA Y BIOLOGIA MOLECULAR "DR. HECTOR N TORRES"
Unidad Ejecutora - UE
artículos
Título:
Nitric oxide potentiation of the homomeric rho1 GABAC receptor function
Autor/es:
GASULLA J, BELTRÁN GONZÁLEZ AN, CALVO DJ.
Revista:
BRITISH JOURNAL OF PHARMACOLOGY
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Lugar: Londres; Año: 2012 vol. 167 p. 1369 - 1377
ISSN:
0007-1188
Resumen:
BACKGROUND AND PURPOSE:
NO is a highly diffusible and
reactive gas produced in the nervous system, which acts as a neuronal
signal mediating physiological or pathological mechanisms. NO can
modulate the activity of neurotransmitter receptors and ion channels,
including NMDA and GABA(A) receptors. In the present work, we examined
whether GABA(C) receptor function can also be regulated by NO.
EXPERIMENTAL APPROACH:
Homomeric
ρ1 GABA(C) receptors were expressed in oocytes and GABA-evoked
responses electrophysiologically recorded in the presence or absence of
the NO donor DEA. Chemical protection of cysteines by selective
sulfhydryl reagents and site-directed mutagenesis were used to determine
the protein residues involved in the actions of NO.
KEY RESULTS:
GABAρ1
receptor responses were significantly enhanced in a dose-dependent,
fast and reversible manner by DEA and the specific NO scavenger CPTIO
prevented these potentiating effects. The ρ1 subunits contain only three
cysteine residues, two extracellular at the Cys-loop (C177 and C191)
and one intracellular (C364). Mutations of C177 and C191 render the ρ1
GABA receptors non-functional, but C364 can be safely exchanged by
alanine (C364A). NEM, N-ethyl maleimide and (2-aminoethyl)
methanethiosulfonate prevented the effects of DEA on GABAρ1 receptors.
Meanwhile, the potentiating effects of DEA on mutant GABAρ1(C364A)
receptors were similar to those observed on wild-type receptors.
CONCLUSIONS AND IMPLICATIONS:
Our results suggest that the function of GABA(C) receptors can be enhanced by NO acting at the extracellular Cys-loop.