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Progress in Neurobiology Jul 2016Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The... (Review)
Review
Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.
Topics: Animals; Dopamine Agents; Humans; Polypharmacology; Receptors, Dopamine
PubMed: 27234980
DOI: 10.1016/j.pneurobio.2016.03.011 -
Pituitary Feb 2017Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands... (Review)
Review
Somatostatin and dopamine receptors are expressed in normal and tumoral somatotroph cells. Upon receptor stimulation, somatostatin and the somatostatin receptor ligands octreotide, lanreotide, and pasireotide, and to a lesser extent, dopamine and the dopamine analogs bromocriptine and cabergoline, suppress growth hormone (GH) secretion from a GH-secreting pituitary somatotroph adenoma. Somatostatin and dopamine receptors are G-protein coupled that inhibit adenylate cyclase activity and cAMP production and reduce intracellular calcium concentration and calcium flux oscillations. Although their main action on somatotroph cells is acute inhibition of GH secretion, they also may inhibit GH production and possibly somatotroph proliferation. These receptors have been reported to create complexes that exhibit functions distinct from that of receptor monomers. Somatostatin suppression of GH is mediated mainly by somatostatin receptor subtype 2 and to a lesser extent by SST5. Human somatostatin receptor subtype 5 has also been shown to harbor mutations associated with GH levels, somatotroph tumor behavior, and somatostatin receptor ligand (SRL) responsiveness. Reviewing current knowledge of somatostatin and dopamine receptor expression and signaling in normal and tumoral somatotroph cells offers insights into mechanisms underlying SRL and dopamine agonist effectiveness in patients with acromegaly.
Topics: Acromegaly; Animals; Humans; Pituitary Neoplasms; Receptors, Dopamine; Somatostatin; Somatotrophs
PubMed: 27900635
DOI: 10.1007/s11102-016-0778-2 -
Molecules (Basel, Switzerland) Jan 2023A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this... (Review)
Review
A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.
Topics: Chemistry, Pharmaceutical; Receptors, G-Protein-Coupled; Phenethylamines; Receptors, Dopamine D2
PubMed: 36677913
DOI: 10.3390/molecules28020855 -
British Journal of Pharmacology Jan 2015The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on... (Review)
Review
The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
Topics: Animals; Humans; Protein Multimerization; Receptors, Dopamine; Signal Transduction
PubMed: 25671228
DOI: 10.1111/bph.12906 -
ACS Nano Aug 2021Polydopamine (PDA)-coated nanoparticles (NPs) are emerging carriers of therapeutic agents for nanomedicine applications due to their biocompatibility and abundant entry...
Polydopamine (PDA)-coated nanoparticles (NPs) are emerging carriers of therapeutic agents for nanomedicine applications due to their biocompatibility and abundant entry to various cell types, yet it remains unknown whether their cellular entry engages cell-surface receptors. As monomeric dopamine (DA) is an endogenous ligand of dopamine receptor and raw ingredient of PDA, we elucidate the interaction between polyethylene glycol-stabilized, PDA-coated gold NPs (Au@PDA@PEG NPs) and dopamine receptors, particularly D2 (D2DR). After proving the binding of Au@PDA@PEG NPs to recombinant and cellular D2DR, we employ antibody blocking, gene knockdown, and gene overexpression to establish the role of D2DR in the cellular uptake of Au@PDA@PEG NPs . By preparing a series of PEG-coated AuNPs that contain different structural analogues of DA (Au@PEG-X NPs), we demonstrate that catechol and amine groups collectively enhance the binding of NPs to D2DR and their cellular uptake. By intravenously injecting Au@PDA@PEG NPs to Balb/c mice, we reveal their binding to D2DR in the liver by competitive inhibition and immunohistochemistry together with their preferential association to D2DR-rich resident Kupffer cells by flow cytometry, a result consistent with the profuse expression of D2DR by resident Kupffer cells. Catechol and amine groups jointly contribute to the preferential association of NPs to D2DR-rich Kupffer cells. Our data highlight the importance of D2DR expression and DA-related functional groups in mediating the cell-nano interactions of PDA-based nanomedicines.
Topics: Mice; Animals; Gold; Metal Nanoparticles; Nanoparticles; Dopamine; Receptors, Dopamine
PubMed: 34379407
DOI: 10.1021/acsnano.1c06081 -
Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications.Biomolecules Feb 2021The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis... (Review)
Review
The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1-D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.
Topics: Animals; Blood Pressure; Diabetes Mellitus; Dopamine; Essential Hypertension; Glomerular Filtration Rate; Homeostasis; Humans; Hyperinsulinism; Kidney; Kidney Diseases; Oxidative Stress; Rats; Receptors, Dopamine; Vasoconstriction
PubMed: 33578816
DOI: 10.3390/biom11020254 -
Life Sciences Nov 2022Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall... (Review)
Review
Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall behavior. Thus, dopamine receptor antagonist antipsychotic drugs are commonly used to treat multiple psychiatric disorders. Although less discussed, these receptors are also expressed in other peripheral organ systems, such as the kidneys, eyes, gastrointestinal tract, and cardiac tissue. Consequently, therapies for certain psychiatric disorders which target dopamine receptors could have unidentified consequences on certain functions of these peripheral tissues. The existence of an intrinsic dopaminergic system in the human heart remains controversial and debated within the literature. Therefore, this review focuses on literature related to dopamine receptors within cardiac tissue, specifically dopamine receptor 3 (D3R), and summarizes the current state of knowledge while highlighting areas of research which may be lacking. Additionally, recent findings regarding crosstalk between D3R and dopamine receptor 1 (D1R) are examined. This review discusses the novel concept of understanding the role of the loss of function of D3R may play in collagen accumulation and cardiac fibrosis, eventually leading to heart failure.
Topics: Animals; Antipsychotic Agents; Dopamine; Dopamine Agonists; Dopamine Antagonists; Fibrosis; Humans; Mammals; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 36041503
DOI: 10.1016/j.lfs.2022.120918 -
Progress in Molecular Biology and... 2023This chapter describes the physiological significance of dopamine receptor endocytosis and the consequence of the receptor signaling. Endocytosis of dopamine receptors...
This chapter describes the physiological significance of dopamine receptor endocytosis and the consequence of the receptor signaling. Endocytosis of dopamine receptors is regulated by many components such as clathrin, β-arrestin, caveolin, and Rab family proteins. The dopamine receptors escape from lysosomal digestion, and their recycling occurs rapidly, reinforcing the dopaminergic signal transduction. In addition, the pathological impact of the receptors interacting with specific proteins has been the focus of much attention. Based on this background, this chapter provides an in-depth understanding of the mechanisms of molecules interacting with dopamine receptors and discusses the potential pharmacotherapeutic targets for α-synucleinopathies and neuropsychiatric disorders.
Topics: Humans; Receptors, Dopamine; Signal Transduction; Endocytosis; Brain; beta-Arrestins
PubMed: 36813367
DOI: 10.1016/bs.pmbts.2022.09.005 -
Nature Communications Dec 2023Neuromodulatory signaling via G protein-coupled receptors (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. The recent development...
Neuromodulatory signaling via G protein-coupled receptors (GPCRs) plays a pivotal role in regulating neural network function and animal behavior. The recent development of optogenetic tools to induce G protein-mediated signaling provides the promise of acute and cell type-specific manipulation of neuromodulatory signals. However, designing and deploying optogenetically functionalized GPCRs (optoXRs) with accurate specificity and activity to mimic endogenous signaling in vivo remains challenging. Here we optimize the design of optoXRs by considering evolutionary conserved GPCR-G protein interactions and demonstrate the feasibility of this approach using two Drosophila Dopamine receptors (optoDopRs). These optoDopRs exhibit high signaling specificity and light sensitivity in vitro. In vivo, we show receptor and cell type-specific effects of dopaminergic signaling in various behaviors, including the ability of optoDopRs to rescue the loss of the endogenous receptors. This work demonstrates that optoXRs can enable optical control of neuromodulatory receptor-specific signaling in functional and behavioral studies.
Topics: Animals; Receptors, Dopamine; Receptors, G-Protein-Coupled; Signal Transduction; GTP-Binding Proteins; Drosophila
PubMed: 38114457
DOI: 10.1038/s41467-023-43970-0 -
Pharmacological Research Sep 2016Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals... (Review)
Review
Actions of the neurotransmitter dopamine in the brain are mediated by dopamine receptors that belong to the superfamily of G protein-coupled receptors (GPCRs). Mammals have five dopamine receptor subtypes, D1 through D5. D1 and D5 couple to Gs/olf and activate adenylyl cyclase, whereas D2, D3, and D4 couple to Gi/o and inhibit it. Most GPCRs upon activation by an agonist are phosphorylated by GPCR kinases (GRKs). The GRK phosphorylation makes receptors high-affinity binding partners for arrestin proteins. Arrestin binding to active phosphorylated receptors stops further G protein activation and promotes receptor internalization, recycling or degradation, thereby regulating their signaling and trafficking. Four non- visual GRKs are expressed in striatal neurons. Here we describe known effects of individual GRKs on dopamine receptors in cell culture and in the two in vivo models of dopamine-mediated signaling: behavioral response to psychostimulants and L-DOPA- induced dyskinesia. Dyskinesia, associated with dopamine super-sensitivity of striatal neurons, is a debilitating side effect of L-DOPA therapy in Parkinson's disease. In vivo, GRK subtypes show greater receptor specificity than in vitro or in cultured cells. Overexpression, knockdown, and knockout of individual GRKs, particularly GRK2 and GRK6, have differential effects on signaling of dopamine receptor subtypes in the brain. Furthermore, deletion of GRK isoforms in select striatal neuronal types differentially affects psychostimulant-induced behaviors. In addition, anti-dyskinetic effect of GRK3 does not require its kinase activity: it is mediated by the binding of its RGS-like domain to Gαq/11, which suppresses Gq/11 signaling. The data demonstrate that the dopamine signaling in defined neuronal types in vivo is regulated by specific and finely orchestrated actions of GRK isoforms.
Topics: Animals; Basal Ganglia; Central Nervous System Stimulants; G-Protein-Coupled Receptor Kinases; Humans; Parkinsonian Disorders; Phosphorylation; Receptors, Dopamine; Signal Transduction
PubMed: 27178731
DOI: 10.1016/j.phrs.2016.05.010