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Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
The disease is, above all, a defect of phagocytic cells which are unable to adhere and move because of the lack of membrane expression of LFA-1, CR3, and pl50,95 molecules. These molecules are heterodimers, sharing a common chain associated with distinct chains.28 The molecular basis of the disease is a quantitative or qualitative abnormality of the chain. The absence of chain synthesis or an abnormal chain leads to no association and no membrane expression.29-31 CR3 and pl50,95 are main components of polymorphonuclear cells (PMN) adhesion, their expression being increased by fusion with the membrane of secondary granules following activation. Such defect leads to severe bacterial infections, the site of which being free of phagocytic cells. In contrast, abnormal PMN accumulate in the bloodstream. Normal lymphocytes express mainly LFA-1. The defective expression of LFA-1 inhibits T-cell adhesion to interacting cells, such as B-cells or target cells for cytotoxic T-cells.32 The clinical consequences of LFA-1 deficiency are limited, perhaps because T-cells with high affinity for antigen do not need additional adhesive molecules. However, in some patients with a complete absence of LFA-1, cytotoxicity is impaired, resulting in an inability to reject HLA mismatched bone marrow, and antibody production to polypeptidic antigens is absent.32
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The GPCRs vary in their ability to couple to and activate distinct G proteins and downstream signaling pathways [9]. Some receptors can activate only one class of G proteins and generate a single class of intracellular signals, while others are more promiscuous and can couple to several classes of G proteins and activate multiple intracellular signals. Furthermore, the formation of receptor homo- or heterodimers (as discussed below) results in variable combinations of signaling events. Collectively, the ability of the GPCRs to signal is regulated at several levels. These include the number of receptors that reside on the cell surface at any given time, alterations in signaling efficiency of the receptors, and formation of functional linkages with different effectors.
TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
Growth factors and other member proteins showing at least 25% homology to TGF-β were included in the TGF-β family. This family includes approximately 40 members, which share similar features, i.e., conserved cysteine residues (such as TGF-β 1–3 and inhibin β polypeptides that have nine characteristic cysteines, bone morphogenetic protein [BMPs] and growth differentiation factors [GDFs] that have seven and remaining BMP15A, GDF3, GDF9 that have six cysteines), which helps in intermolecular interaction for ligand dimerization and structural integrity. Ligands exist both as homo- and heterodimers. The members of this superfamily include transforming growth factor β 1–3 (TGF-βs), inhibins and activins, BMPs, Müllerian inhibiting substance (MIS), also called anti-Müllerian hormone (AMH), GDFs and glial cell line-derived neurotrophic factor (GDNF) (7). These subfamilies have more members (Table 11.1), which have different cell functions depending upon their type, concentration, target tissue and developmental stage (8).
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
Many receptors, especially GPCRs, function as dimers. Dimerization affects agonist binding and functional response and enriches the pallet of possible signaling patterns, including biphasic functional responses that may even take a shape of a bell. In effect, functional-response curves are complex. However, a combination of various receptors into heterodimers brings more possible pharmacological targets varying in pharmacological properties and thus new ways for selective therapeutic targeting. Individual physiological processes are executed by a dedicated organ or tissue. As expression patterns of individual receptors vary among tissues and organs the probability of variation in heterodimerization increases. This gives a chance for tissue-specific pharmacotherapy of desired physiological functions held by the targeted tissue.
The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
Published in Expert Opinion on Therapeutic Targets, 2020
Antonela S Asad, Alejandro J Nicola Candia, Nazareno Gonzalez, Camila F Zuccato, Adriana Seilicovich, Marianela Candolfi
PRLR homodimers and heterodimers between long and short isoforms, associated via the transmembrane domain, have been reported to be constitutively expressed in the cell surface in humans [42]. However, PRLR heterodimers are functionally inactive even in the presence of PRL [42]. According to the groups of Dufau and Akopian, PRLR heterodimers may inhibit the signaling through PRLR long isoform [42,43]. PRLR short isoforms contain the Box1 binding site for JAK2 and MAPK proteins but lack the Box2 binding site for STAT, as well as its downstream phosphorylation sites [44]. Upon stimulation with PRL, the formation of heterodimers between PRLR short and long isoforms is predicted to sequester functional long isoform monomers into inactive heterodimers with the short isoform [44]. Thus, it has been proposed that PRLR short isoforms would act as negative regulators of the long isoform to stop its signaling over time [44]. In addition, PRLR and growth hormone (GH) receptor (GHR) are homologous transmembrane cytokine receptors and hence have similar structure. In humans, PRLR may be activated by both PRL and GH [45]. Co-immunoprecipitation assays have revealed that GH signaling in breast cancer cells is largely mediated by PRLR homodimers as well as GHR-PRLR heterodimers [45]. Latest studies indicate that these heterodimers would actually consist of complexes between GHR homodimers and PRLR homodimers [46].
SLC12A2: a new gene associated with autosomal dominant Non-Syndromic hearing loss in humans
Published in Hearing, Balance and Communication, 2020
A. Morgan, G. Pelliccione, U. Ambrosetti, D. Dell’Orco, G. Girotto
In order to better evaluate the pathogenic effect of the identified variant, an in silico protein modelling has been performed. Based on the recently resolved cryo-EM three dimensional structure of the zebrafish Na–K–Cl cotransporter [8], which shares 77.6% sequence identity in the 284-1212 region, the protein encoded by SLC12A2 is predicted to form a homodimer that crosses the membrane integrally by the transmembrane domain (TMD), thus allowing the inflow of ions. Two cytosolic domains (CTD), one per monomer, regulate the transport and trafficking (Figure 1(E)). The substitution p.(T1144N) replaces a solvent-exposed Thr residue with a polar Asn. In homologous potassium-chloride co-transporters, the C-terminal cytosolic domain is involved in transport activation [9] and dimerisation appears to play a role in the regulatory mechanism. Moreover, phosphorylation of specific residues at the C-terminus is associated with transporter deactivation [10]. It is therefore reasonable to speculate that the substitution identified in our case may have complex functional consequences yet to be determined, creating a complex molecular scenario, in which homodimers as well as heterodimers may form as a consequence of the heterozygous condition.