Major Classes Of Receptors Research Articles

Differential Affinities of Visual Arrestin, βArrestin1, and βArrestin2 for G Protein-coupled Receptors Delineate Two Major Classes of Receptors

Visual arrestin, betaarrestin1, and betaarrestin2 comprise a family of intracellular proteins that desensitize G protein-coupled receptors (GPCRs). In addition, betaarrestin1 and betaarrestin2 target desensitized receptors to clathrin-coated pits for endocytosis. Whether arrestins differ in their ability to interact with GPCRs in cells is not known. In this study, we visualize the interaction of arrestin family members with GPCRs in real time and in live cells using green fluorescent protein-tagged arrestins. In the absence of agonist, visual arrestin and betaarrestin1 were found in both the cytoplasm and nucleus of HEK-293 cells, whereas betaarrestin2 was found only in the cytoplasm. Analysis of agonist-mediated arrestin translocation to multiple GPCRs identified two major classes of receptors. Class A receptors (beta2 adrenergic receptor, mu opioid receptor, endothelin type A receptor, dopamine D1A receptor, and alpha1b adrenergic receptor) bound betaarrestin2 with higher affinity than betaarrestin1 and did not interact with visual arrestin. In contrast, class B receptors (angiotensin II type 1A receptor, neurotensin receptor 1, vasopressin V2 receptor, thyrotropin-releasing hormone receptor, and substance P receptor) bound both betaarrestin isoforms with similar high affinities and also interacted with visual arrestin. Switching the carboxyl-terminal tails of class A and class B receptors completely reversed the affinity of each receptor for the visual and non-visual arrestins. In addition, exchanging the betaarrestin1 and betaarrestin2 carboxyl termini reversed their extent of binding to class A receptors as well as their subcellular distribution. These results reveal for the first time marked differences in the ability of arrestin family members to bind GPCRs at the plasma membrane. Moreover, they show that visual arrestin can interact in cells with GPCRs other than rhodopsin. These findings suggest that GPCR signaling may be differentially regulated depending on the cellular complement of arrestin isoforms and the ability of arrestins to interact with other cellular proteins.

Crossing the border – laminins outside the basement membrane

Laminins constitute a growing protein family, classically found in the basement membrane. From the time of their discovery in the late 1970s, it has been clear that laminins, which polymerize into networks, do not only fulfil a structural role in basement membranes, and early cell-biological studies pointed to the potent biological effects of laminins on cell behaviour. Two major classes of receptors mediating these effects are integrins and dystroglycan. Defects in laminin chains have been found to be the underlying cause of epidermolysis bullosa and congenital muscular dystrophy.

Roles ofN-Glycans with α2,6 as well as α2,3 Linked Sialic Acid in Infection by Polyoma Virus

Specific glycosylation inhibitors were used to show that N-glycans, and not O-glycans or glycolipids, constitute the major class of receptors on 3T3 cells for polyoma virus. Sialic acid (SA)-specific lectins were used in attempts to confirm the expected SA linkage on N-linked glycans. A lectin specific for α2,6 linked SA, a non-receptor type, was slightly more effective in blocking infection than a lectin specific for α2,3 linked SA which corresponds to the known receptor specificity. Possible explanations are suggested for this unexpected result.

Intrathecal and epidural opioids

NTRASPINAL ANESTHESIA was first described by Bier and others of surgical anesthesia following intrathecal injection of the local anesthetic, cocaine. 1 Near the turn of the century, opioids (morphine) and o~z-adrenergic agonists (epinephrine) were injected intrathecally 2 but were soon abandoned because they did not produce surgical anesthesia. Use of these agents was rediscovered in the late 1970s, when they produced analgesia, not anesthesia, after intrathecal injection in animals) Within a few years, this led to clinical use of intrathecal morphine for analgesia. 4 Over the last 15 years, epidural and spinal injection of opioids have been reported for the treatment of acute and chronic pain in thousands of research reports and are a common practice in modern anesthesia care. The purpose of this article is to review intrathecal and epidural opioids in terms of their mechanism of action and clinical use, their interactions with other anesthetics and analgesics, and their effect on patient outcome, with a focus on perioperative use. MECHANISM OF ACTION Opioids act on three major classes of receptors, classified originally by pharmacological means, and termed mu (#), delta (5), and kappa (K). The endogenous ligands for these receptors are endorphins (#), enkephalins (5), and dynorphins (K), although at high enough concentrations, each of these peptides can interact with all opioid receptors. Pharmacological and molecular techniques have now distinguished several subtypes of each of these receptors, although all clinically used opioids are capable of stimulating all opioid receptor types and subtypes.

Synaptic Integrins in Developing, Adult, and Mutant Muscle: Selective Association of α1, α7A, and α7B Integrins with the Neuromuscular Junction

Differentiation of both pre- and postsynaptic structures at the skeletal neuromuscular junction is organized by the basal lamina that occupies the synaptic cleft. As β1 integrins are a major class of receptors for basal lamina components, we stained muscles with antibodies to the 10 integrin α subunits known to form dimers with β1, to determine if any of these molecules were concentrated at synaptic sites on muscle fibers. In both developing and adult muscle, the integrin α1 chain was selectively associated with presynaptic cells (Schwann cells and/or nerve terminals), while α7 was present on both synaptic and extrasynaptic portions of the muscle fiber surface. Thus α1 and α7 integrins are present in synaptic membranes. Expression of the α7 chain was analyzed further by staining with antibodies specific for three alternatively spliced products of the α7 gene (A, B, and C), all of which were expressed in muscle. The α7A and α7B isoforms were confined to synaptic sites in adult muscle, while α7C was present both synaptically and extrasynaptically. In developing muscle, α7A appeared postnatally and specifically at the synapse; α7B was present throughout the muscle fiber perinatally, becoming confined to the synapse in the second postnatal week; and α7C was present extrasynaptically both perinatally and in adulthood. Thus, two of the α7 integrins are synapse-specific, and all three show distinct spatiotemporal patterns of expression within a single cell type. Finally, we asked whether perturbation of laminin expression affected the distribution of the α7 integrins. In normal mice, laminin β2 is concentrated in synaptic basal lamina. In β2-null mutant mice, α7A was still present at synaptic sites, but α7B was absent. This result provides genetic evidence that basal lamina composition is a determinant of integrin distribution.

Cross-talk between tyrosine kinase and G-protein-linked receptors. Phosphorylation of beta 2-adrenergic receptors in response to insulin.

Protein kinases play a pivotal role in the propagation and modulation of transmembrane signaling pathways. Two major classes of receptors, G-protein-linked and tyrosine kinase receptors not only propagate signals but also are substrates for phosphorylation in response to stimulation by agonist ligands. Insulin (operating via tyrosine kinase receptors) and catecholamines (operating by G-protein-linked receptors) are counterregulatory with respect to lipid and carbohydrate metabolism. How, on a cellular level, these two distinct classes of receptors may cross-regulate each other remains controversial. In the present work we identify a novel cross-talk between members of two distinct classes of receptors, tyrosine kinase (insulin) and G-protein-linked (beta-adrenergic) receptors. Treatment of DDT1 MF-2 hamster vas deferens smooth muscle cells with insulin promoted a marked attenuation (desensitization) of beta-adrenergic receptor-mediated activation of adenylylcyclase. Measured by immune precipitation of beta 2-adrenergic receptors from cells metabolically labeled with [32P]orthophosphate, the basal state of receptor phosphorylation was increased 2-fold by insulin. Phosphoamino acid analysis revealed that for insulin-stimulated cells, the beta 2-adrenergic receptors showed increased phosphorylation on tyrosyl and decreased phosphorylation on threonyl residues. Phosphorylation of the beta-adrenergic receptor was rapid and peaked at 30 min following stimulation of cells by insulin. beta-Adrenergic receptor phosphorylation and attenuation of catecholamine-sensitive adenylylcyclase provide a biochemical basis for the counterregulatory effects of insulin upon catecholamine action.

2 - Cellular Mechanisms of Acid Secretion

Current ideas about the parietal cell are presented in the model shown in Figure 6; the cell is illustrated both in resting and stimulated states. The basal-lateral surface contains three major receptor classes mediated by either cyclic AMP responses or Ca2+ changes, Ca2+ channels and a Ca2+ pump, and a variety of ion transport pathways such as Na+:H+ and Cl-:HCO-3 exchange, a K+ conductance, a postulated NaKCl2 cotransport and the (Na+ + K+)ATPase. At rest, the tubulovesicles contain the (H+ + K+)ATPase. In the stimulated state, the apical (secretory canalicular) membrane contains a K+ and Cl- conductance as well as the (H+ + K+)ATPase. There is also a change in cytoskeletal arrangement associated with stimulation.