Adenosine receptors: G protein-mediated signalling and the role of accessory proteins

Klinger, Markus; Freissmuth, Michael; Nanoff, Christian

doi:10.1016/s0898-6568(01)00235-2

Cited by 242 publications

(171 citation statements)

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“…Interaction with Ca o 2ϩ may change the conformation of GABA B R (11,12). There are increasing reports (42,45,46) that the ligand-dependent conformational change of a GPCR leads to modulation of closely associated adaptor proteins or GPCRs without the aid of G proteins. Such ''direct'' modulation is a possible mechanism because mGluR1 was obtained by coimmunoprecipitation for GBR1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Tabata

Araishi

Hashimoto

et al. 2004

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

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Type B ␥-aminobutyric acid receptor (GABABR) is a G proteincoupled receptor that regulates neurotransmitter release and neuronal excitability throughout the brain. In various neurons, GABA BRs are concentrated at excitatory synapses. Although these receptors are assumed to respond to GABA spillover from neighboring inhibitory synapses, their function is not fully understood. Here we show a previously undescribed function of GABA BR exerted independent of GABA. In cerebellar Purkinje cells, interaction of GABA BR with extracellular Ca 2؉ (Ca o 2؉ ) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor 1 (mGluR1). mGluR1 sensitization is clearly mediated by GABA BR because it is absent in GABABR1 subunitknockout cells. However, the mGluR1 sensitization does not require G i/o proteins that mediate the GABABR's classical functions. Moreover, coimmunoprecipitation reveals complex formation between GABA BR and mGluR1 in the cerebellum. These findings demonstrate that GABA BR can act as Ca o 2؉ -dependent cofactors to enhance neuronal metabotropic glutamate signaling.T he type B ␥-aminobutyric acid receptor (GABA B R) is a G protein-coupled receptor (GPCR) distributed throughout the brain (1-3). GABA B R regulates neurotransmitter release and neuronal excitability via G i/o proteins (4). In the classic view, GABA B R responds to GABA released from inhibitory presynaptic terminals (4). However, in some central neurons including cerebellar Purkinje cells, postsynaptic GABA B Rs are concentrated perisynaptically at the excitatory synapses and present sparsely at the inhibitory synapses (5-7). Because GABA B Rs are insensitive to the excitatory neurotransmitter glutamate, a physiological role of GABA B R at excitatory synapses was assumed to depend on ␥-aminobutyric acid (GABA) spillover from neighboring inhibitory synapses (8, 9).The extracellular domain of GABA B R has an amino acid sequence homology to that of Ca 2ϩ -sensing receptor (CaR) (10). Some studies in the heterologous expression systems (11,12) revealed that GABA B R indeed interacts with extracellular Ca 2ϩ (Ca o 2ϩ ). Point mutation experiments indicate that the proximity of the GABA-binding site of GABA B R1 subunit (GBR1) is responsible for this interaction (11). Although Ca o 2ϩ -GABA B R interaction does not activate G proteins (12), it causes a remarkable conformational change of GABA B R as Ca o 2ϩ allosterically shifts GABA-GABA B R affinity (11,12 (22-25), and developmental synapse elimination (24, 26). In cerebellar Purkinje cells, mGluR1 colocalizes with GABA B R at the annuli of the dendritic spines innervated by excitatory parallel fibers (7,27). We have previously shown that mGluR1 signaling in Purkinje cells is enhanced as a consequence of interaction between Ca o 2ϩ and an unknown surface molecule(s) (28). For the reasons mentioned above, we considered GABA B R as a likely candidate for such a surface molecule.In Purkinje cells, mGluR1 outnumbers the other mGluR subtypes (16) and operates an inward ca...

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Section: Discussionmentioning

confidence: 99%

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Tabata

Araishi

Hashimoto

et al. 2004

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

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“…The source of aqueous humour adenosine is not clear, but could include secretion from the ciliary body, ectonucleotidase catabolism of ATP released by ciliary epithelium (Mitchell et al, 1999;Matsuoka et al, 2002;Eltzschig et al, 2003), and similarly from ectonucleotidase catabolism of ATP release by the corneal endothelium (Soltau et al, 1993). Based on the known affinities of the receptor subtypes to adenosine (Klinger et al, 2002), the aqueous humour concentration of adenosine would favour A 1 receptor stimulation (decrease [cAMP] i ). However, the local concentration of adenosine at the endothelial surface is not known and could be much higher, in which case A 2 receptors could also be stimulated.…”

Section: Introductionmentioning

confidence: 99%

Characterization of adenosine receptors in bovine corneal endothelium

Tan-Allen

Sun

Bonanno

2005

Experimental Eye Research

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Previous studies indicated that adenosine can increase [cAMP] i and stimulate fluid transport by corneal endothelium. The purpose of this study was to determine which adenosine receptor subtype(s) are expressed and to examine their functional roles in modulating [cAMP] Western blot (WB) confirmed the presence of A 2b (∼50 kDa) and A 1 (∼40 kDa) in fresh and cultured BCE. Ten micromolar adenosine increased [cAMP] i by 2·7-fold over control and this was inhibited 66% by 10 μM alloxazine, a specific A 2b blocker. A 1 activation with 1 μM N 6 -CPA (a specific A 1 agonist) or 100 nM adenosine decreased [cAMP] i by 23 and 6%, respectively. Adenosine had no effect on [Ca 2+ ] i mobilization. Indirect immunofluorescence localized A 2b receptors to the lateral membrane and A 1 to the apical surface in cultured BCE. Adenosine significantly increased apical Cl − permeability by 2·2 times and this effect was nearly abolished by DMPX (10 μM), a general A 2 blocker. Adenosine-induced membrane depolarization was also inhibited by 33% (n=6) in the presence of alloxazine. Bovine corneal endothelium expresses functional A 1 and A 2b adenosine receptors. A 1 , preferentially activated at <1 μM adenosine, acts to decrease [cAMP] i and A 2b , activated at >1 μM adenosine, increase [cAMP] i .

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“…The surface receptors for adenosine, with the exception of A3 receptors, are antagonized by methylxanthines (van Gallen et al 1994, Klinger et al 2002, while the actions via ''P'' sites are blocked by adenosine transport inhibitors. Studies with knockout mutants have revealed many important functions of adenosine receptors such as the regulation of inflammation (Ohta and Sitkovsky 2001).…”

Section: Introductionmentioning

confidence: 99%

Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

Paes‐de‐Carvalho¹

2002

An. Acad. Bras. Ciênc.

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The nucleoside adenosine plays an important role as a neurotransmitter or neuromodulator in the central nervous system, including the retina. In the present paper we review compelling evidence showing that adenosine is a signaling molecule in the developing retina. In the chick retina, adenosine transporters are present since early stages of development before the appearance of adenosine A1 receptors modulating dopamine-dependent adenylate cyclase activity orA2 receptors that directly activate the enzyme. Experiments using retinal cell cultures revealed that adenosine is taken up by specific cell populations that when stimulated by depolarization or neurotransmitters such as dopamine or glutamate, release the nucleoside through calciumdependent transporter-mediated mechanisms. The presence of adenosine in the extracellular medium and the long-term activation of adenosine receptors is able to regulate the survival of retinal neurons and blocks glutamate excitoxicity. Thus, adenosine besides working as a neurotransmitter or neuromodulator in the mature retina, is considered as an important signaling molecule during retinal development having important functions such as regulation of neuronal survival and differentiation.

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Adenosine receptors: G protein-mediated signalling and the role of accessory proteins

Cited by 242 publications

References 104 publications

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Characterization of adenosine receptors in bovine corneal endothelium

Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

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Adenosine receptors: G protein-mediated signalling and the role of accessory proteins

Cited by 242 publications

References 104 publications

Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Characterization of adenosine receptors in bovine corneal endothelium

Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

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Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA