PubMed | National Institute for Physiological science, University of Barcelona, Unitat de Farmacologia, University of Castilla - La Mancha and 2 more.
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014
Group I metabotropic glutamate (mGlu) receptors regulate hippocampal CA1 pyramidal neuron excitability via Ca(2+) wave-dependent activation of small-conductance Ca(2+)-activated K(+) (SK) channels. Here, we show that mGlu5 receptors and SK2 channels coassemble in heterologous coexpression systems and in rat brain. Further, in cotransfected cells or rat primary hippocampal neurons, mGlu5 receptor stimulation activated apamin-sensitive SK2-mediated K(+) currents. In addition, coexpression of mGlu5 receptors and SK2 channels promoted plasma membrane targeting of both proteins and correlated with increased mGlu5 receptor function that was unexpectedly blocked by apamin. These results demonstrate a reciprocal functional interaction between mGlu5 receptors and SK2 channels that reflects their molecular coassembly.
Borroto-Escuela D.O.,Karolinska Institutet |
Marcellino D.,Karolinska Institutet |
Narvaez M.,University of Malaga |
Flajolet M.,Rockefeller University |
And 4 more authors.
Biochemical and Biophysical Research Communications | Year: 2010
Evidence exists that the adenosine receptor A2AR and the dopamine receptor D2R form constitutive heteromers in living cells. Mass spectrometry and pull-down data showed that an arginine-rich domain of the D2R third intracellular loop binds via electrostatic interactions to a specific motif of the A2AR C-terminal tail. It has been indicated that the phosphorylated serine 374 might represent an important residue in this motif. In the present study, it was found that a point mutation of serine 374 to alanine reduced the A2AR ability to interact with D2R. Also, this point mutation abolished the A2AR-mediated inhibition of both the D2R high affinity agonist binding and signaling. These results point to a key role of serine 374 in the A2AR-D2R interface. All together these results indicate that by targeting A2AR serine 374 it will be possible to allosterically modulate A2AR-D2R function, thus representing a new approach for therapeutically modulate D2R function. © 2010 Elsevier Inc.
Lopez-Hernandez T.,University of Barcelona |
Sirisi S.,University of Barcelona |
Sirisi S.,Research Center En Red Of Enfermedades Rara Ciberer |
Capdevila-Nortes X.,University of Barcelona |
And 11 more authors.
Human Molecular Genetics | Year: 2011
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in MLC1 or GLIALCAM. The GLIALCAM gene product functions as an MLC1 beta-subunit. We aim to further clarify the molecular mechanisms of MLC caused by mutations in MLC1 or GLIALCAM. For this purpose, we analyzed a human post-mortem brain obtained from an MLC patient, who was homozygous for a missense mutation (S69L) in MLC1. We showed that this mutation affects the stability of MLC1 in vitro and reduces MLC1 protein levels in the brain to almost undetectable. However, the amount of GlialCAM and its localization were nearly unaffected, indicating that MLC1 is not necessary for GlialCAM expression or tar- geting. These findings were supported by experiments in primary astrocytes and in heterologous cells. In addition, we demonstrated that MLC1 and GlialCAM form homo- and hetero-complexes and that MLC-causing mutations in GLIALCAM mainly reduce the formation of GlialCAM homo-complexes, leading to a defect in the trafficking of GlialCAM alone to cell junctions. GLIALCAM mutations also affect the trafficking of its associ- ated molecule MLC1, explaining why GLIALCAM and MLC1 mutations lead to the same disease: MLC. © The Author 2011. Published by Oxford University Press.
Vazquez-Carrera M.,Unitat de Farmacologia
Drugs of the Future | Year: 2012
GFT-505 is a first-in-class dual peroxisome proliferator-activated receptor PPAR-α/δ agonist being developed by Genfit for the potential treatment of atherosclerosis, dyslipidemia, type 2 diabetes, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Preclinical and phase II trials have demonstrated that GFT-505 reduces plasma triglyceride levels, increases HDL cholesterol and improves insulin sensitivity and markers of liver dysfunction associated with NAFLD/NASH. No significant toxicological or safety concerns have been identified in studies in animals and humans. The reported efficacy and safety data for GFT-505 currently available support the continued development of the compound. At the time of publication, phase III trials were under way, but no results have been reported. The use of a dual PPAR- α/δ agonist may provide unique benefits for the prevention and treatment of several risk factors (insulin resistance, type 2 diabetes, atherogenic dyslipidemia and NAFLD/NASH) of cardiovascular diseases and metabolic syndrome. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.