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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The general association of GPCRs with the heterotrimeric G proteins was introduced at the beginning of this chapter (Table 2.2). The DAR-associated Gα subunits are divided into several classes: Gαs/olf and Gαio (associated with stimulation and inhibition of AC, respectively), Gαq/11 (associated with the activation of phospholipase C; PLC), and Gα12/13 (associated with the activation of RhoA as well as with guanylate cyclase; GC). Other effectors/second messengers reported to be activated by DAR agonists have not been clearly assigned to specific G protein subunits or act independent of the G proteins [9]. Both the α and βγ subunits can activate multiple cell-specific effectors that include AC, GC, phosphodiesterases (PDEs), PLC, nitric oxide synthase (NOS), transporters and various ion channels. These, in turn, regulate second messengers such as cAMP, cGMP, diacylglycerol (DAG), inositol triphosphate (IP3), NO, arachidonic acid, and a variety of ions, ultimately leading to an integrated physiological response. The G protein-induced signal is terminated by the RGS proteins, which enhance the intrinsic GTPase activity of the Gα subunit [48]. Upon hydrolysis of the bound GTP to GDP, the α and βγ subunits reassociate, and the inactive G protein becomes linked again to the receptor.
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
It is a cell surface receptor (membrane receptors or transmembrane receptors) that is made up of specialized integral membrane proteins that takes part in communication between the cell and the extracellular environment of the cell. It is a receptor with seven transmembrane helical segments and distributed across nearly all of the body’s organs and tissues. In the cell, GPCRs plays as a key role in signal transducers that makes GPCRs key regulatory elements in a broad range of normal and pathological processes [1]. In addition to the cell surface, GPCRs are present in the endoplasmic reticulum, Golgi apparatus, nuclear membrane and even inside the nucleus itself [2–4]. The variety of endogenous ligands (stimuli) activate GPCRs including biogenic amines, neuropeptides, amino acids, ions, hormones, chemokines, lipid-derived mediators, proteases peptides, proteins [5], protons (H+) and ions (Ca2+) [6]. GPCRs lacks internal enzymatic activity and are coupled to heterotrimeric guanosine nucleotide–binding protein (G protein), which consist of Gα, Gβ and Gγ subunits. The binding of ligand(s) stabilizes the occupied GPCR in an active signaling conformation during which the heterotrimeric G-proteins dissociate in GTP-bound Gα and Gβγ subunits (Figure 1.1). These regulate the activity of several enzymes such as adenylate cyclase, phospholipase C (PLC) isoforms and kinases, resulting in the generation of intracellular second messengers that control cellular functions, which are responsible for triggering different signaling responses [7].
Inter- and Intracellular Signaling in Plant Cells with Participation of Neurotransmitters (Biomediators)
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Signaling mechanism at the cellular level is similar with known for mammalians and includes following processes: (1) the binding of aforementioned substances with appropriate receptors on the plasmatic membrane (intercellular signaling) or on the outer membrane of organelle (intracellular signaling); (2) the conformation changes of the excited receptors transfer into the cell or organelle interior; and (3) the signal transfer through cytoplasm or the organelle interior occurs by electric changes, perhaps, the action potential spreading or by systems of secondary messengers (cyclic AMP, or GMP, calcium ions, etc.). A special role belongs to G-proteins (heterotrimeric protein with Gα, Gβ/Gγ subunits) and constitutes one of the most important components of the cell signaling cascade (Tuteja 2009). G Protein Coupled Receptors (GPCRs) perceive many extracellular signals, transduce them to heterotrimeric G proteins and further transduce these signals intracellularly to appropriate downstream effectors, thereby playing an important role in various signaling pathways. GPCRs exist as a superfamily of integral membrane protein receptors that contain seven transmembrane α-helical regions, which bind to a wide range of ligands. The end of the signaling is realized in various metabolic responses. More known data are concerned with cAMP (Gehring 2010) or inositol triphosphate (Stevenson et al. 2000) in plants.
Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity
Published in Platelets, 2021
Delia I. Fernández, Marijke J. E. Kuijpers, Johan W. M. Heemskerk
As in their name, GPCRs couple to heterotrimeric G-proteins, comprising of α, β, and γ subunits, each of them present different isoforms. For all GPCRs, receptor binding causes a switch from the inactive (GDP binding) to the active (GTP binding) form of the Gα subunits. The most relevant Gα-subunits for platelet Ca2+ signaling and ensuing processes are: (i) Gαq (raising cytosolic Ca2+ via PLCβ isoforms) and (ii) Gαs (lowering cytosolic Ca2+ via cAMP production) (Figure 1). The other G-proteins, Gα12/13 (activating the monomeric GTPase, RhoA) and Gαi (suppressing cAMP production and activating phosphatidylinositol 3-kinases via βγ subunit), modulate the Ca2+ signal only indirectly, as detailed below [1,7]. Of the dozens of GPCRs expressed by platelets, most well studied in relation to Ca2+ signaling are the receptors for thrombin (PAR1, PAR4), ADP (P2Y1, P2Y12), and thromboxane A2 (TP). Dysfunctional mutations of most of these receptors have been described [8,9], as detailed below.
Editorial: structure–function relationships of tyrosine kinase- and tyrosine phosphatase-linked receptors in platelets and megakaryocytes
Published in Platelets, 2021
Platelets are regulated by two major classes of surface receptors which can be distinguished by the number of transmembrane chains. Seven transmembrane receptors signal through heterotrimeric G proteins and are regulated by so-called soluble agonists. The family of G protein-coupled receptors is divided into stimulatory receptors, which regulate Gq, G12/13 and Gi family G proteins, and inhibitory receptors, which regulate Gs family G proteins. Examples include the receptors for ADP, thrombin, and prostacyclin. The group of single transmembrane receptors is much larger and diverse, with a greater range of functions including adhesion, signaling, and membrane organization. Several of these proteins form larger complexes composed of distinct chains as exemplified by the major signaling receptor for collagen, the GPVI-Fc receptor chain (FcR) complex, with GPVI harboring the binding site for collagen, and FcR the signaling arm. Regulation of many single transmembrane proteins is mediated through dimerization and higher order clustering, rather than through a conformational change.
Genetic and molecular determinants of prostate cancer among Iranian patients: An update
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Majid Ghayour-Mobarhan, Gordon A. Ferns, Meysam Moghbeli
The G protein coupled receptor (GPCR) family are cell surface receptors involved in a variety of cellular processes. G proteins are mediators that transfer the signals from the cell surface receptor to intracellular signaling pathways involved in cell growth and transcription [31]. Prostate-specific G-protein coupled receptor (PSGR) is expressed mainly in human prostate epithelium, which is upregulated in PCa [32]. PSGR upregulation is synergistically associated with phosphatase and tensin homolog (PTEN) loss during PCa progression and metastasis [33]. LGR4, a member of the GPCRs, is involved in epithelial mesenchymal transition (EMT) and metastasis of PCa cells through the PI3K/Akt signaling pathway [34,35]. Moreover, GPR160 is associated with apoptosis and cell cycle arrest; GPR160 silencing significantly increased the levels of CASP1 in PCa cells [36]. Initial GPCR signal transduction is triggered by activation of heterotrimeric G proteins, which activate messenger systems, small GTPases, and kinase cascades. These proteins are composed of several subunits (α, β, and γ). The G protein subunit beta 3 (GNB3) encodes the β3 subunit of G proteins [37]. When the role of rs5443 single nucleotide polymorphisms (SNP) in PCa progression was evaluated in a subpopulation of Iranian patients, a significant correlation between PCa and T allele of the GNB3 C825T SNP was observed. Moreover, the presence of the GNB3 825 T allele was significantly related to tumor grade and stage [38].