Guanine-nucleotide binding regulatory proteins as targets for novel drugs

Research output: Contribution to journalConference Contribution

Abstract

Guanine-nucleotide regulatory binding proteins (G-proteins) serve to transduce information from agonist-bound receptor complexes to either effector enzymes or ion-channels. Drugs that perturb the function of G-proteins may do so by one of four mechanisms. (i) They may exert negative intrinsic activity toward the G-protein. For instance, we have shown that incubation of isolated plasma-membranes with the beta-adrenoceptor blocking drug sotalol blocked both GTP-stimulated and isoprenaline-stimulated adenylyl cyclase. This suggests that the empty beta-adrenoceptor is capable of tonically stimulating G(s-alpha) and therefore adenylyl cyclase; that is, empty beta-adrenoceptors promote GDP-GTP exchange. (ii) They may perturb the GDP-GTP exchange reaction. For instance, certain PDE inhibitors, including SKF 94836 and rolipram, stimulate a marked increase in the pertussis toxin-catalysed NAD+-dependent ADP-ribosylation of G(i-alpha). This effect is similar to that of GDP, which promotes stabilisation of the alpha-beta-gamma holomer of G(i). The effect of these PDE inhibitors is completely reversed by GppNHp, which triggers alpha-beta-gamma dissociation by binding to the guanine-nucleotide binding domain of the G-protein. PDE inhibitors may serve as a class of drugs which perturb GDP-GTP exchange. (iii) They may trigger uncoupling of receptor-G-protein complexes. For instance, the polycationic drug mastoparan binds to the C-terminal end of the G-protein and mimics the effect of receptor activation by promoting GTP-gamma-S binding, a reduction in pertussis toxin-catalysed ADP-ribosylation, and inhibition of adenylyl cyclase activity. Other agents, such as polyanionic drugs, bind to the receptor to promote uncoupling of receptor-mediated activation of certain G-proteins. (iv) They may alter the cross-talk mechanisms that operate between different receptor signalling systems. For instance, protein kinase C promotes the phosphorylation and inactivation of G(i). This leads to an unopposed stimulation of adenylyl cyclase via G(S) and, therefore, enhanced sensitivity to agents such as glucagon. Protein kinase C inhibitors may be usefully exploited to modulate these processes which appear to be abberant in certain disease-states.

LanguageEnglish
Pages27-36
Number of pages10
JournalProceedings - Royal Society of Edinburgh. Section B: Natural environment
Volume99
Issue number1-2
Publication statusPublished - 1992

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GTP-Binding Proteins
Carrier Proteins
Guanosine Triphosphate
Adenylyl Cyclases
Pharmaceutical Preparations
Adrenergic Receptors
Pertussis Toxin
Adenosine Diphosphate
Protein Kinase C
Gs GTP-Binding Protein alpha Subunits
Rolipram
Guanosine 5'-O-(3-Thiotriphosphate)
Sotalol
Guanine Nucleotides
Protein C Inhibitor
Protein Kinase Inhibitors
Glucagon
Ion Channels
Isoproterenol
NAD

Keywords

  • adenylate-cyclase
  • phosphorylation state
  • signal transduction
  • platelet membranes
  • cholera-toxin
  • alpha-subunit
  • kinase-c
  • gi
  • identification
  • hepatocytes

Cite this

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title = "Guanine-nucleotide binding regulatory proteins as targets for novel drugs",
abstract = "Guanine-nucleotide regulatory binding proteins (G-proteins) serve to transduce information from agonist-bound receptor complexes to either effector enzymes or ion-channels. Drugs that perturb the function of G-proteins may do so by one of four mechanisms. (i) They may exert negative intrinsic activity toward the G-protein. For instance, we have shown that incubation of isolated plasma-membranes with the beta-adrenoceptor blocking drug sotalol blocked both GTP-stimulated and isoprenaline-stimulated adenylyl cyclase. This suggests that the empty beta-adrenoceptor is capable of tonically stimulating G(s-alpha) and therefore adenylyl cyclase; that is, empty beta-adrenoceptors promote GDP-GTP exchange. (ii) They may perturb the GDP-GTP exchange reaction. For instance, certain PDE inhibitors, including SKF 94836 and rolipram, stimulate a marked increase in the pertussis toxin-catalysed NAD+-dependent ADP-ribosylation of G(i-alpha). This effect is similar to that of GDP, which promotes stabilisation of the alpha-beta-gamma holomer of G(i). The effect of these PDE inhibitors is completely reversed by GppNHp, which triggers alpha-beta-gamma dissociation by binding to the guanine-nucleotide binding domain of the G-protein. PDE inhibitors may serve as a class of drugs which perturb GDP-GTP exchange. (iii) They may trigger uncoupling of receptor-G-protein complexes. For instance, the polycationic drug mastoparan binds to the C-terminal end of the G-protein and mimics the effect of receptor activation by promoting GTP-gamma-S binding, a reduction in pertussis toxin-catalysed ADP-ribosylation, and inhibition of adenylyl cyclase activity. Other agents, such as polyanionic drugs, bind to the receptor to promote uncoupling of receptor-mediated activation of certain G-proteins. (iv) They may alter the cross-talk mechanisms that operate between different receptor signalling systems. For instance, protein kinase C promotes the phosphorylation and inactivation of G(i). This leads to an unopposed stimulation of adenylyl cyclase via G(S) and, therefore, enhanced sensitivity to agents such as glucagon. Protein kinase C inhibitors may be usefully exploited to modulate these processes which appear to be abberant in certain disease-states.",
keywords = "adenylate-cyclase, phosphorylation state, signal transduction, platelet membranes, cholera-toxin, alpha-subunit, kinase-c, gi, identification, hepatocytes",
author = "Nigel Pyne",
year = "1992",
language = "English",
volume = "99",
pages = "27--36",
journal = "Proceedings - Royal Society of Edinburgh. Section B: Natural environment",
issn = "0308-2113",
number = "1-2",

}

Guanine-nucleotide binding regulatory proteins as targets for novel drugs. / Pyne, Nigel .

In: Proceedings - Royal Society of Edinburgh. Section B: Natural environment , Vol. 99, No. 1-2, 1992, p. 27-36.

Research output: Contribution to journalConference Contribution

TY - JOUR

T1 - Guanine-nucleotide binding regulatory proteins as targets for novel drugs

AU - Pyne, Nigel

PY - 1992

Y1 - 1992

N2 - Guanine-nucleotide regulatory binding proteins (G-proteins) serve to transduce information from agonist-bound receptor complexes to either effector enzymes or ion-channels. Drugs that perturb the function of G-proteins may do so by one of four mechanisms. (i) They may exert negative intrinsic activity toward the G-protein. For instance, we have shown that incubation of isolated plasma-membranes with the beta-adrenoceptor blocking drug sotalol blocked both GTP-stimulated and isoprenaline-stimulated adenylyl cyclase. This suggests that the empty beta-adrenoceptor is capable of tonically stimulating G(s-alpha) and therefore adenylyl cyclase; that is, empty beta-adrenoceptors promote GDP-GTP exchange. (ii) They may perturb the GDP-GTP exchange reaction. For instance, certain PDE inhibitors, including SKF 94836 and rolipram, stimulate a marked increase in the pertussis toxin-catalysed NAD+-dependent ADP-ribosylation of G(i-alpha). This effect is similar to that of GDP, which promotes stabilisation of the alpha-beta-gamma holomer of G(i). The effect of these PDE inhibitors is completely reversed by GppNHp, which triggers alpha-beta-gamma dissociation by binding to the guanine-nucleotide binding domain of the G-protein. PDE inhibitors may serve as a class of drugs which perturb GDP-GTP exchange. (iii) They may trigger uncoupling of receptor-G-protein complexes. For instance, the polycationic drug mastoparan binds to the C-terminal end of the G-protein and mimics the effect of receptor activation by promoting GTP-gamma-S binding, a reduction in pertussis toxin-catalysed ADP-ribosylation, and inhibition of adenylyl cyclase activity. Other agents, such as polyanionic drugs, bind to the receptor to promote uncoupling of receptor-mediated activation of certain G-proteins. (iv) They may alter the cross-talk mechanisms that operate between different receptor signalling systems. For instance, protein kinase C promotes the phosphorylation and inactivation of G(i). This leads to an unopposed stimulation of adenylyl cyclase via G(S) and, therefore, enhanced sensitivity to agents such as glucagon. Protein kinase C inhibitors may be usefully exploited to modulate these processes which appear to be abberant in certain disease-states.

AB - Guanine-nucleotide regulatory binding proteins (G-proteins) serve to transduce information from agonist-bound receptor complexes to either effector enzymes or ion-channels. Drugs that perturb the function of G-proteins may do so by one of four mechanisms. (i) They may exert negative intrinsic activity toward the G-protein. For instance, we have shown that incubation of isolated plasma-membranes with the beta-adrenoceptor blocking drug sotalol blocked both GTP-stimulated and isoprenaline-stimulated adenylyl cyclase. This suggests that the empty beta-adrenoceptor is capable of tonically stimulating G(s-alpha) and therefore adenylyl cyclase; that is, empty beta-adrenoceptors promote GDP-GTP exchange. (ii) They may perturb the GDP-GTP exchange reaction. For instance, certain PDE inhibitors, including SKF 94836 and rolipram, stimulate a marked increase in the pertussis toxin-catalysed NAD+-dependent ADP-ribosylation of G(i-alpha). This effect is similar to that of GDP, which promotes stabilisation of the alpha-beta-gamma holomer of G(i). The effect of these PDE inhibitors is completely reversed by GppNHp, which triggers alpha-beta-gamma dissociation by binding to the guanine-nucleotide binding domain of the G-protein. PDE inhibitors may serve as a class of drugs which perturb GDP-GTP exchange. (iii) They may trigger uncoupling of receptor-G-protein complexes. For instance, the polycationic drug mastoparan binds to the C-terminal end of the G-protein and mimics the effect of receptor activation by promoting GTP-gamma-S binding, a reduction in pertussis toxin-catalysed ADP-ribosylation, and inhibition of adenylyl cyclase activity. Other agents, such as polyanionic drugs, bind to the receptor to promote uncoupling of receptor-mediated activation of certain G-proteins. (iv) They may alter the cross-talk mechanisms that operate between different receptor signalling systems. For instance, protein kinase C promotes the phosphorylation and inactivation of G(i). This leads to an unopposed stimulation of adenylyl cyclase via G(S) and, therefore, enhanced sensitivity to agents such as glucagon. Protein kinase C inhibitors may be usefully exploited to modulate these processes which appear to be abberant in certain disease-states.

KW - adenylate-cyclase

KW - phosphorylation state

KW - signal transduction

KW - platelet membranes

KW - cholera-toxin

KW - alpha-subunit

KW - kinase-c

KW - gi

KW - identification

KW - hepatocytes

UR - http://www.rsescotlandfoundation.org.uk/publications/proceedings_b/

M3 - Conference Contribution

VL - 99

SP - 27

EP - 36

JO - Proceedings - Royal Society of Edinburgh. Section B: Natural environment

T2 - Proceedings - Royal Society of Edinburgh. Section B: Natural environment

JF - Proceedings - Royal Society of Edinburgh. Section B: Natural environment

SN - 0308-2113

IS - 1-2

ER -