Real-world evidence in Alzheimer's disease: The ROADMAP Data Cube.

Introduction: The ROADMAP project aimed to provide an integrated overview of European real-world data on Alzheimer's disease (AD) across the disease spectrum.

Methods: Metadata were identified from data sources in catalogs of European AD projects. Priority outcomes for different stakeholders were identified through systematic literature review, patient and public consultations, and stakeholder surveys.

Coassembly and coupling of SK2 channels and mGlu5 receptors.

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.

Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs.

Dissecting the conserved NPxxY motif of the M3 muscarinic acetylcholine receptor: critical role of Asp-7.49 for receptor signaling and multiprotein complex formation.

Acetylcholine challenge produces M(3) muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M(3) muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation.

The M(5) muscarinic acetylcholine receptor third intracellular loop regulates receptor function and oligomerization.

Besides some pharmacological, biochemical and biophysical evidences support the contention that muscarinic acetylcholine receptors can form homo- and heterodimers, the existence of specific M(3) and M(5) muscarinic receptors oligomers in living cells is a new concept. Interestingly, this phenomenon might have relevance in lymphocytic cholinergic function since both T- and B-cells naturally express high levels of these two receptor subtypes. Here, by means of co-immunoprecipitation and bioluminescence resonance energy transfer methods we demonstrated that M(3) and M(5) muscarinic receptors could form constitutive homo- and heterodimers in transiently transfected HEK-293T cells.