G proteins as drug targets

Höller, Christoph; Freissmuth, Michael; Nanoff, Christian

doi:10.1007/s000180050288

Cited by 68 publications

(54 citation statements)

References 143 publications

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“…D2N and several other receptor-derived peptides have been shown to elicit modest exchange factor activity in vitro toward specific G␣ subunits and are therefore thought to represent direct receptor/G␣ engagement sites acted on during GPCR-mediated activation (12). When used alone (at maximally effective concentrations; see refs 9 and 11), KB-752 and D2N each stimulated the rate of GTP␥S binding (Fig.…”

Section: Resultsmentioning

confidence: 93%

RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity

Johnston

Siderovski

2007

Proc. Natl. Acad. Sci. U.S.A.

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The authors wish to note the following: "In our paper, a cocrystal structure at 2.2 Å resolution was described of the heterotrimeric G-protein alpha subunit Gαi1 bound to two peptides: one from an artificial sequence that promotes nucleotide exchange (KB-752) and a second peptide (D2N) from the third intracellular loop of the D2 dopamine receptor (PDB ID code 2HLB). Further examination of the unbiased electron density map has revealed that, while electron density exists for the KB-752 peptide, there is a lack of clear and continuous electron density for the D2N receptor peptide in the complex. Because the structural model represents a major conclusion of the paper but is unsupported by the experimental electron density map, we wish to retract the paper. Both authors deeply regret this mistake and sincerely apologize."

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Section: Resultsmentioning

confidence: 93%

RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity

Johnston

Siderovski

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings support that in the AHR, ET response was mediated by the ET B receptor, whereas in the PHR, the conventional receptors were not involved. In an attempt to identify whether the receptor activated by ETs in the PHR was a GPCR, tissues were pretreated with 500 nM SMN (a G protein inhibitor at this concentration) (22). SMN modified TH activity neither in the AHR nor in the PHR, but it abolished ET-induced reduction of TH activity in the AHR and ETinduced increase of the enzyme activity in the PHR (Fig.…”

Section: Resultsmentioning

confidence: 99%

Long-term modulation of tyrosine hydroxylase activity and expression by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

Perfume

Nabhen²,

Barrera³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Perfume G, Nabhen SL, Riquelme Barrera K, Otero MG, Bianciotti LG, Vatta MS. Long-term modulation of tyrosine hydroxylase activity and expression by endothelin 1 and 3 in the rat anterior and posterior hypothalamus. Am J Physiol Regul Integr Comp Physiol 294: R905-R914, 2008. First published December 19, 2007 doi:10.1152/ajpregu.00555.2007.-Brain catecholamines are involved in the regulation of biological functions, including cardiovascular activity. The hypothalamus presents areas with high density of catecholaminergic neurons and the endothelin system. Two hypothalamic regions intimately related with the cardiovascular control are distinguished: the anterior (AHR) and posterior (PHR) hypothalamus, considered to be sympathoinhibitory and sympathoexcitatory regions, respectively. We previously reported that endothelins (ETs) are involved in the short-term tyrosine hydroxylase (TH) regulation in both the AHR and PHR. TH is crucial for catecholaminergic transmission and is tightly regulated by well-characterized mechanisms. In the present study, we sought to establish the effects and underlying mechanisms of ET-1 and ET-3 on TH long-term modulation. Results showed that in the AHR, ETs decreased TH activity through ETB receptor activation coupled to the nitric oxide, phosphoinositide, and CaMK-II pathways. They also reduced total TH level and TH phosphorylated forms (Ser 19 and 40). Conversely, in the PHR, ETs increased TH activity through a G protein-coupled receptor, likely an atypical ET receptor or the ETC receptor, which stimulated the phosphoinositide and adenylyl cyclase pathways, as well as CaMK-II. ETs also increased total TH level and the Ser 19, 31, and 40 phosphorylated sites of the enzyme. These findings support that ETs are involved in the long-term regulation of TH activity, leading to reduced sympathoinhibition in the AHR and increased sympathoexcitation in the PHR. Present and previous studies may partially explain the cardiovascular effects produced by ETs when applied to the brain. catecholamines; endothelin receptors; central nervous system ENDOTHELINS (ETS) ARE VASOACTIVE peptides originally isolated from cultured porcine endothelial cells (56). They constitute a family of three 21-amino acid isopeptides termed ET-1, ET-2, and ET-3 (10, 23). ETs exert their biological effects through the activation of ET A and ET B receptors that are G proteincoupled receptors (GPCRs) (10,34,38). Despite these two well pharmacologically characterized GPCRs, several pharmacological and functional studies support the existence of additional ET receptors. The finding of atypical responses in the presence of selective ET A and ET B antagonists and/or agonists observed in different studies built up the term atypical receptors (ET AX or ET BX ) to refer to those receptors that mediate ET responses but fail to be identified by using selective antagonists or agonists of the conventional ET A and ET B receptors (12,20,36,38,41). In addition, a third receptor subtype named ET C that displays high affinity for ET-3 was ...

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“…Earlier work has already established that the D2N peptide directly activates G proteins of the G i/o class and uncouples the D 2 receptor (10). In this context, it is worth noting that the receptomimetic peptide mastoparan, which directly activates G i/o proteins (25), also binds CaM with high (nanomolar) affinity, a property shared by other insect venoms (26). Ca 2ϩ /CaM blocks G protein activation by D2N in a noncompetitive manner; in addition, Ca 2ϩ /CaM inhibits the guanine nucleotide exchange reaction promoted by the D 2 receptor in membranes.…”

Section: Immobilization Of G␣ I1 On a Calmodulin-sepharose Requires Tmentioning

confidence: 99%

Binding of Calmodulin to the D2-Dopamine Receptor Reduces Receptor Signaling by Arresting the G Protein Activation Switch

Bofill-Cardona¹,

Kudlacek²,

Yang³

et al. 2000

Journal of Biological Chemistry

125

127

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D 1 and D 2 receptors, the "classical" dopamine receptor subtypes, are abundantly expressed in the basal ganglia and are important targets in pharmacotherapy, yet the basis for their neuromodulatory effects is not well understood at the cellular level. The D 2 -dopamine receptor is found (as an autoreceptor) on presynaptic nerve terminals of nigrostriatal projections and, postsynaptically, on the medium spiny neuron, the predominant nerve cell of the neostriatum (2). The excitatory drive for the medium spiny neuron is provided by glutamatergic afferents which through NMDA receptors trigger Ca 2ϩ influx (3). Hence, neuronal signal transduction by dopamine receptors proceeds in the presence of oscillating intracellular Ca 2ϩ concentrations and there is reason to assume that the signaling mechanism is interrelated with the intracellular Ca 2ϩ level. Calmodulin (CaM), 1 a small acidic protein, can be considered the primary decoder of Ca 2ϩ information in the cell. CaM has a Ca 2ϩ affinity of 10 Ϫ6 M and thus acts as a switch when the concentration rises from a resting value of ϳ10 Ϫ7 M to 10Calmodulin can be activated by persistent elevation of intracellular Ca 2ϩ and by Ca 2ϩ oscillations, as they occur on repeated depolarizations of nerve cells (4). It has long been known that major effectors regulated by the D 2 -dopamine receptor can be regulated by Ca 2ϩ and that these effector molecules are enriched in striatal neurons. In these instances, increases in Ca 2ϩ levels elicit effects similar to D 2 receptor activation. For example, Ca 2ϩ reduces the intracellular cAMP levels by inhibiting adenylyl cyclase type V (and type VI) and by activating CaM-sensitive phosphodiesterases, which break down cAMP; both type V adenylyl cyclase (5, 6) and a 63-kDa isoform of phosphodiesterase (PDE1B1) are expressed in striatal neurons (7,8). Another example for the cross-talk between D 2 receptor signaling and Ca 2ϩ /CaM is the target protein DARPP-32, an inhibitor of protein phosphatase 1. DARPP-32 is dephosphorylated on D 2 -dopamine receptor activation and thus becomes active; this effect is strongly enhanced by Ca 2ϩ /CaM through activation of calcineurin (9). These examples suggest that the signal transduced by Ca 2ϩ /CaM and signaling initiated by the intracellular D 2 receptor overlap and may add to each other.We have found in the primary peptide sequence of the human D 2 -dopamine receptor a CaM-binding motif, which is located in the NH 2 terminus of the third cytoplasmic loop of the receptor. In the present work, we report that CaM can convey * This work was supported by Austrian Science Foundation Grants P13097 (to M. F.) and P14273 (to C. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.¶ To whom correspondence should be addressed. E-mail: christian. nanoff@univie.ac.at.

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G proteins as drug targets

Cited by 68 publications

References 143 publications

RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity

RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity

Long-term modulation of tyrosine hydroxylase activity and expression by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

Binding of Calmodulin to the D2-Dopamine Receptor Reduces Receptor Signaling by Arresting the G Protein Activation Switch

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G proteins as drug targets

Cited by 68 publications

References 143 publications

RETRACTED: Structural basis for nucleotide exchange on Gα i subunits and receptor coupling specificity

RETRACTED: Structural basis for nucleotide exchange on Gα i subunits and receptor coupling specificity

Long-term modulation of tyrosine hydroxylase activity and expression by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

Binding of Calmodulin to the D2-Dopamine Receptor Reduces Receptor Signaling by Arresting the G Protein Activation Switch

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RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity

RETRACTED: Structural basis for nucleotide exchange on Gα _i subunits and receptor coupling specificity