Dataset Information

G Protein-Coupled Receptors Regulated by Membrane Potential.

ABSTRACT: G protein-coupled receptors (GPCRs) are involved in a vast majority of signal transduction processes. Although they span the cell membrane, they have not been considered to be regulated by the membrane potential. Numerous studies over the last two decades have demonstrated that several GPCRs, including muscarinic, adrenergic, dopaminergic, and glutamatergic receptors, are voltage regulated. Following these observations, an effort was made to elucidate the molecular basis for this regulatory effect. In this review, we will describe the advances in understanding the voltage dependence of GPCRs, the suggested molecular mechanisms that underlie this phenomenon, and the possible physiological roles that it may play.

SUBMITTER: David D

PROVIDER: S-EPMC9696401 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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G Protein-Coupled Receptors Regulated by Membrane Potential.

David Dekel D Bentulila Ziv Z Tauber Merav M Ben-Chaim Yair Y

International journal of molecular sciences 20221112 22

G protein-coupled receptors (GPCRs) are involved in a vast majority of signal transduction processes. Although they span the cell membrane, they have not been considered to be regulated by the membrane potential. Numerous studies over the last two decades have demonstrated that several GPCRs, including muscarinic, adrenergic, dopaminergic, and glutamatergic receptors, are voltage regulated. Following these observations, an effort was made to elucidate the molecular basis for this regulatory effe ...[more]

PMID: 36430466

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Project description:Detection and transduction of environmental signals, constitute a prerequisite for successful parasite invasion; i.e., Leishmania transmission, survival, pathogenesis and disease manifestation and dissemination, with diverse molecules functioning as inter-cellular signaling ligands. Receptors [i.e., G protein-coupled receptors (GPCRs)] and their associated transduction mechanisms, well conserved through evolution, specialize in this function. However, canonical GPCR-related signal transduction systems have not been described in Leishmania, although orthologs, with reduced domains and function, have been identified in Trypanosomatidae. These inter-cellular communication means seem to be essential for multicellular and unicellular organism's survival. GPCRs are flexible in their molecular architecture and may interact with the so-called receptor activity-modifying proteins (RAMPs), which modulate their function, changing GPCRs pharmacology, acting as chaperones and regulating signaling and/or trafficking in a receptor-dependent manner. In the skin, vasoactive- and neuro- peptides released in response to the noxious stimuli represented by the insect bite may trigger parasite physiological responses, for example, chemotaxis. For instance, in Leishmania (V.) braziliensis, sensory [Substance P, SP, chemoattractant] and autonomic [Vasoactive Intestinal Peptide, VIP, and Neuropeptide Y, NPY, chemorepellent] neuropeptides at physiological levels stimulate in vitro effects on parasite taxis. VIP and NPY chemotactic effects are impaired by their corresponding receptor antagonists, suggesting that the stimulated responses might be mediated by putative GPCRs (with essential conserved receptor domains); the effect of SP is blocked by [(D-Pro 2, D-Trp7,9]-Substance P (10-6 M)] suggesting that it might be mediated by neurokinin-1 transmembrane receptors. Additionally, vasoactive molecules like Calcitonin Gene-Related Peptide [CGRP] and Adrenomedullin [AM], exert a chemorepellent effect and increase the expression of a 24 kDa band recognized in western blot analysis by (human-)-RAMP-2 antibodies. In-silico search oriented towards GPCRs-like receptors and signaling cascades detected a RAMP-2-aligned sequence corresponding to Leishmania folylpolyglutamate synthase and a RAMP-3 aligned protein, a hypothetical Leishmania protein with yet unknown function, suggesting that in Leishmania, CGRP and AM activities may be modulated by RAMP- (-2) and (-3) homologs. The possible presence of proteins and molecules potentially involved in GPCRs cascades, i.e., RAMPs, signpost conservation of ancient signaling systems associated with responses, fundamental for cell survival, (i.e., taxis and migration) and may constitute an open field for description of pharmacophores against Leishmania parasites.

Project description:The ligands of certain G-protein coupled receptors (GPCRs) are membrane soluble and reach their target from the lipid bilayer. Lipid composition and dynamics will therefore modulate the activity of these receptors, but specific roles of lipid components, including the ubiquitous cholesterol (Chol), are not clear. We have probed the organization and dynamics of such a lipid-bilayer-penetrating ligand, the endogenous ligand for the κ-opioid receptor (KOR) dynorphin A (1-17) (DynA), using molecular dynamics (MD) simulations of DynA in cholesterol-depleted and cholesterol-enriched model membranes. DynA is found to penetrate deep inside fluid dimyristoylphosphatidylcholine (DMPC) bilayers, and resides with its N-terminal helix at ∼6 Å away from the bilayer midplane, in a tilted orientation, at an ∼50° angle with respect to the membrane normal. In contrast, DynA inside DMPC/Chol membranes with 20% cholesterol (DMPC/Chol) is situated with its helical segment ∼5 A higher, i.e., closer to the lipid/water interface and in a relatively vertical orientation. The DMPC membrane shows greater thinning around the insertion and permits a stronger influx of water inside the hydrocarbon core than the DMPC/Chol membranes. Relating these results to data about key GPCR residues that have been implicated in interactions with membrane-inserting GPCR ligands, we conclude that the position of DynA in DMPC/Chol, but not in pure DMPC, correlates with generally proposed GPCR ligand entry pathways. Our predictions provide a possible mechanistic explanation as to why DynA binding to KOR, and the subsequent activation of the receptor, is facilitated in cholesterol-enriched environments. A quantitative description of DynA-induced membrane deformations is obtained with a continuum theory of membrane deformations (CTMD) that is based on hydrophobic matching. Comparison with the MD data reveals the significance of the lipid tail packing energy contribution in the DMPC/Chol mixtures in predicting equilibrium membrane shape around DynA. On this basis, specific corrections are introduced to this energy term within the CTMD framework, thereby extending the applicability of the CTMD framework to lipid raft mixtures and their interactions with GPCR proteins and their ligands.

Dataset Information

G Protein-Coupled Receptors Regulated by Membrane Potential.

Publications

G Protein-Coupled Receptors Regulated by Membrane Potential.

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