CD3/T‐cell receptor coupling to a pertussis and cholera toxin‐insensitive G‐protein

Kvanta, Anders; Nordstedt, Christer; Ploeg, Ingeborg van der; Jondal, Mikael; Fredholm, Bertil B.

doi:10.1016/0014-5793(89)80791-4

Cited by 11 publications

(5 citation statements)

References 27 publications

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“…In glial cells the positive effect of PKC activation can, however, be counteracted by an inhibitory effect of strong increases in intracellular calcium Fredholm 1992, 1993;Balmforth et al 1992). A similar effect is seen in lymphocytes (Fredholm et al 1987a;Nordstedt et al , 1989Kvanta et al 1989). In these cells it could be shown that the stimulatory effect of PKC activation predominantly occurs downstream of the receptor.…”

Section: A 2b Interactionsmentioning

confidence: 81%

Structure and function of adenosine receptors and their genes

Fredholm

Arslan

Halldner

et al. 2000

Naunyn-Schmied Arch Pharmacol

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511

497

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Four adenosine receptors have been cloned from many mammalian and some non-mammalian species. In each case the translated part of the receptor is encoded by two separate exons. Two separate promoters regulate the A1 receptor expression, and a similar situation may pertain also for the other receptors. The receptors are expressed in a cell and tissue specific manner, even though A1 and A2B receptors are found in many different cell types. Emerging data indicate that the receptor protein is targeted to specific parts of the cell. A1 and A3 receptors activate the Gi family of G proteins, whereas A2A and A2B receptors activate the Gs family. However, other G proteins can also be activated even though the physiological significance of this is unknown. Following the activation of G proteins several cellular effector pathways can be affected. Signaling via adenosine receptors is also known to interact in functionally important ways with signaling initiated via other receptors.

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Section: A 2b Interactionsmentioning

confidence: 81%

Structure and function of adenosine receptors and their genes

Fredholm

Arslan

Halldner

et al. 2000

Naunyn-Schmied Arch Pharmacol

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511

497

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“…Indirect evidences of Gprotein implication was brought forward by experiments showing a T-cell activating effect of GTP analogs [16] or fluoroaluminate ions [ 13,161. The use of bacterial toxins to explore the role of G-proteins in the activation of intact T-cells has led to somewhat conflicting results [13,[17][18][19][20]251, however the implication of G-proteins in various steps of T-cell activation has been more directly documented by cell-free experiments showing that triggering of CD3/TcR by specific antibodies [21], or IL-1 receptor occupancy [23,24], stimulate both GTP analogue binding and GTPase activity of membranes. Furthermore, membrane receptors for ConA have been shown to be physically linked to G-protein(s) able to stimulate a cytosolic phospholipase C in murine thymocytes [22].…”

Section: Discussionmentioning

confidence: 99%

“…been characterized (38,39). Gi(s) might be excluded as candidates for relaying CD3/TcR triggering, as they are recognized substrates for pertussis toxin and would not account for the lack of sensitivity of cell-activation to this toxin [21,38]. Gi might however transduce a cyclase-inhibiting signal issuing from Con A receptors [22].…”

Section: Discussionmentioning

confidence: 99%

“…Gi might however transduce a cyclase-inhibiting signal issuing from Con A receptors [22]. 'Small' (about 25 kDa) G-proteins are proposed by several authors to be responsible for transduction of CD3/TcR signal leading to PIP2-phospholipase C stimulation and Ca2+ level rise [21,22,38]. Finally, the cholera toxin-sensitive, pertussis toxin-insensitive Gs would mediate the negative control of activation by relaying adenylate cyclase-stimulating signals, responsible for sustained CAMP elevation, e.g.…”

Section: Discussionmentioning

confidence: 99%

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Impaired G‐proteins and cyclic nucleotide phosphodiesterase activity in T‐lymphocytes from patients with sarcoidosis

Némoz

Prigent

Aloui

et al. 1993

Eur J Clin Investigation

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Among the various immune abnormalities which characterize active sarcoidosis, a low proliferative response of peripheral blood lymphocytes to mitogenic lectins has long been observed. Since membrane-associated G-proteins are very likely to be crucial elements in lectin signal transduction, we investigated the binding of 5'-guanylylimidodiphosphate (GppNHp), a non hydrolyzable GTP analogue, to blood total lymphocyte membranes and to blood T-lymphocyte membranes from patients with active sarcoidosis, and from healthy control subjects. GppNHp binding was markedly decreased in peripheral cells from patients with sarcoidosis as compared to controls, suggesting the occurrence of a defect at the level of G-protein(s). A further characterization of G-proteins in these cells by means of ADP-ribose-labelling in the presence of bacterial toxins brought forward a significant decrease in the labelling of a 40 kDa protein, the major pertussis toxin substrate, in membranes from sarcoid patients, while the labelling of the major 44 kDa cholera toxin substrate proved to be unchanged with respect to control membranes. It is hypothesized that, in sarcoid lymphocytes, a defect in the negative control of adenylate cyclase mediated by the inhibitory G-protein Gi, prevents the lowering of cAMP necessary to normal mitogenic response of blood lymphocytes to stimulation. cAMP degradation by the specialized enzyme phosphodiesterase constitutes another critical step in the control of cAMP levels. Both cAMP and cGMP phosphodiesterase activities were found decreased in blood total lymphocyte preparations from sarcoid patients. With purified T-cells, although the mean cAMP and cGMP phosphodiesterase activities from sarcoid patients were found more markedly decreased with respect to healthy donors, only the decrease in cGMP phosphodiesterase was found statistically significant. The role these defects in cyclic nucleotide degradation potentially play in the disturbance of blood lymphocytes response associated with sarcoidosis is discussed.

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“…This soluble tyrosine kinase shows considerable structural homologies with both p56'" and pp60c-8rc. It has been repeatedly demonstrated that T-cell activation leads to stimulation of GTPase activity, which might suggest the involvement of a G-protein [71]. However, this GTPase clearly differs from several of the classical heterotrimeric G-proteins, and it was very recently shown that T-cell activation leads to the stimulation of p21r"a [72].…”

Section: Receptor Interactions In Lymphocytesmentioning

confidence: 99%

Diversity in receptor signalling: cellular individuality and the search for selective drugs

Fredholm

1991

Journal of Internal Medicine

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Historical backgroundA major aim in pharmacology is to find drugs that cure or alleviate symptoms of disease while having no other significant effects on the organism. Historically, an almost mystical relationship between a disease and a therapeutic agent or procedure has often been assumed. One still prevalent approach to therapeutic specificity was pioneered by Hahneman (1 755-1847), who suggested that the specificity of the pharmacological principle could be increased by 'potentiation '. The relatively widespread acceptance of so-called ' homeopathic ' medicine could be partly due to the fact that it produced less severe iatrogenic disease than a number of other methods. However, it was recently reported that the efficacy of the homeopathic preparation could not be ascribed entirely to a placebo effect [ 11. either in the alleviation of hayfever or in the production of side-effects. In several other studies which compared homeopathic remedies with

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CD3/T‐cell receptor coupling to a pertussis and cholera toxin‐insensitive G‐protein

Cited by 11 publications

References 27 publications

Structure and function of adenosine receptors and their genes

Structure and function of adenosine receptors and their genes

Impaired G‐proteins and cyclic nucleotide phosphodiesterase activity in T‐lymphocytes from patients with sarcoidosis

Diversity in receptor signalling: cellular individuality and the search for selective drugs

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