Function of γ-Aminobutyric Acid Receptor/Channel ρ1 Subunits In Spinal Cord

Zheng, Wei; Xie, Wenrui; Zhang, Jiianhua; Strong, Judith A.; Ling, Wang; Yu, Lei; Xu, Ming; Luo, Lu

doi:10.1074/jbc.m307930200

Cited by 40 publications

(25 citation statements)

References 57 publications

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“…First, electron microscopy revealed 1 immunoreactivity at synaptic junctions. Second, spontaneous IPSPs were partially antagonized by TPMPA, suggesting that they were mediated in part by 1-containing receptors because the presence of the 1 subunit is essential for TPMPA-mediated reductions of GABA responses in mouse spinal cord (Zheng et al, 2003). Third, 1 and ␥2 subunits coimmunoprecipitate (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons

Milligan¹,

Buckley²,

Garret³

et al. 2004

J. Neurosci.

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Fast inhibition in the nervous system is commonly mediated by GABA A receptors comprised of 2␣/2␤/1␥ subunits. In contrast, GABA C receptors containing only subunits (1-3) have been predominantly detected in the retina. However, here using reverse transcription-PCR and in situ hybridization we show that mRNA encoding the 1 subunit is highly expressed in brainstem neurons. Immunohistochemistry localized the 1 subunit to neurons at light and electron microscopic levels, where it was detected at synaptic junctions. Application of the GABA C receptor agonist cis-4-aminocrotonic acid (100 -800 M) requires the 1 subunit to elicit responses, which surprisingly are blocked independently by antagonists to GABA A (bicuculline, 10 M) and GABA C [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA); 40 -160 M] receptors. Responses to GABA C agonists were also enhanced by the GABA A receptor modulator pentobarbitone (300 M). Spontaneous and evoked IPSPs were reduced in amplitude but never abolished by TPMPA, but were completely blocked by bicuculline. We therefore tested the hypothesis that GABA A and GABA C subunits formed a heteromeric receptor. Immunohistochemistry indicated that 1 and ␣1 subunits were colocalized at light and electron microscopic levels. Electrophysiology revealed that responses to GABA C receptor agonists were enhanced by the GABA A receptor modulator zolpidem (500 nM), which acts on the ␣1 subunit when the ␥2 subunit is also present. Finally, coimmunoprecipitation indicated that the 1 subunit formed complexes that also contained ␣1 and ␥2 subunits. Taken together these separate lines of evidence suggest that the effects of GABA in central neurons can be mediated by heteromeric complexes of GABA A and GABA C receptor subunits.

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Section: Discussionmentioning

confidence: 99%

Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons

Milligan¹,

Buckley²,

Garret³

et al. 2004

J. Neurosci.

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“…Lately, the 1 subunit was immunolocalized in DRG neurons and in lamina I and II of the spinal superficial dorsal horn, and 1-containing receptors have been shown to modulate nociceptive transmission (8). However, it is still unclear if 1 forms homooligomeric receptors or if it associates with GABA A subunits to form a hybrid receptor/channel (8). P2X 2 receptors are also expressed in these neuronal populations and have also been shown to be involved in modulation of pain/sensory pathways in spinal cord (44).…”

Section: Discussionmentioning

confidence: 99%

“…Recent data suggest that a 1 subunit could co-assemble with a GABA A subunit (5,6). Neuronal ATP and GABA C ionotropic receptors are involved in fast excitatory and inhibitory synaptic transmission, respectively, and display overlapping distribution in many regions of the nervous system, including DRG, dorsal horn of the spinal cord (7,8), retina (9 -13), hippocampus (14 -15), cerebellum (14,16), and anterior pituitary (17,18).…”

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confidence: 99%

“…Because P2X and 1/GABA receptors are co-expressed in the central nervous system (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), we investigated potential molecular and functional interactions between these two types of transmitter-gated channels in heterologous expression systems. We report here an intracellular inhibitory cross-talk between P2X 2 and GABA C 1 receptors.…”

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confidence: 99%

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Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Boué‐Grabot

Émerit

Toulmé

et al. 2004

Journal of Biological Chemistry

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␥-Aminobutyric-acid (GABA) and ATP ionotropic receptors represent two structurally and functionally different classes of neurotransmitter-gated channels involved in fast synaptic transmission. We demonstrate here that, when the inhibitory 1/GABA and the excitatory P2X 2 receptor channels are co-expressed in Xenopus oocytes, activation of one channel reduces the currents mediated by the other one. This reciprocal inhibitory cross-talk is a receptor-mediated phenomenon independent of agonist cross-modulation, membrane potential, direction of ionic flux, or channel densities. Functional interaction is disrupted when the cytoplasmic C-terminal domain of P2X 2 is deleted or in competition experiments with minigenes coding for the Cterminal domain of P2X 2 or the main intracellular loop of 1 subunits. We also show a physical interaction between P2X 2 and 1 receptors expressed in oocytes and the co-clustering of these receptors in transfected hippocampal neurons. Co-expression with P2X 2 induces retargeting and recruitment of mainly intracellular 1/ GABA receptors to surface clusters. Therefore, molecular and functional cross-talk between inhibitory and excitatory ligand-gated channels may regulate synaptic strength both by activity-dependent current occlusion and synaptic receptors co-trafficking.Neuronal activity is regulated by a number of transmitters acting on different receptor types (1). Fast neurotransmission is achieved through different classes of transmitter-gated channels, including the P2X and nicotinic receptor superfamilies (1, 2). The family of P2X ATP-gated cation channels is composed of seven genes coding for subunits with two transmembrane domains, intracellular N and C termini, and a large extracellular loop (2). The nicotinic superfamily includes the GABA-gated 1 channels along with the acetylcholine, 5-HT 3 , and glycine receptors that share several structural features, including a large extracellular N-terminal domain, four hydrophobic transmembrane domains (M1-M4), and a long cytoplasmic loop connecting M3 and M4 (1). GABA receptor channels have been classified into two subtypes based on their pharmacological properties. GABA A receptors are inhibited by bicuculline, whereas GABA C receptors are insensitive to this antagonist (1). Diversity of GABA A receptors is achieved by pentameric assembly of multiple subunits, including ␣1-6, ␤1-3, ␥1-3, ␦, , and ⑀. GABA C receptors are composed of 1-3 subunits that can assemble into homo-oligomers (3, 4). Recent data suggest that a 1 subunit could co-assemble with a GABA A subunit (5, 6). Neuronal ATP and GABA C ionotropic receptors are involved in fast excitatory and inhibitory synaptic transmission, respectively, and display overlapping distribution in many regions of the nervous system, including DRG, dorsal horn of the spinal cord (7, 8), retina (9 -13), hippocampus (14 -15), cerebellum (14, 16), and anterior pituitary (17, 18).Recently, Jo and co-workers described ATP and GABA corelease from the same axon terminals into the dorsal horn of the spinal ...

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“…Besides being expressed in the retina, GABA C receptor ρ subunits were also found in other brain regions such as the hippocampus, cerebellum and the superior colliculus, as well as in the spinal cord [33][34][35][36]. Furthermore, ρ subunits were detected in secretory cells of the pituitary, in neurons of the gastrointestinal tract and in a neuroendocrine tumour cell line of the gut [37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Tax1-binding protein 1 is expressed in the retina and interacts with the GABAC receptor ρ1 subunit

Ulrich

Seeber

Becker

et al. 2006

Biochemical Journal

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Macromolecular signalling complexes that link neurotransmitter receptors to functionally and structurally associated proteins play an important role in the regulation of neurotransmission. Thus the identification of proteins binding to neurotransmitter receptors describes molecular mechanisms of synaptic signal transduction. To identify interacting proteins of GABA C (where GABA is γ -aminobutyric acid) receptors in the retina, we used antibodies specific for GABA C receptor ρ1-3 subunits. Analysis of immunoprecipitated proteins by MALDI-TOF MS (matrixassisted laser-desorption ionization-time-of-flight MS) identified the liver regeneration-related protein 2 that is identical with amino acids 253-813 of the Tax1BP1 (Tax1-binding protein 1). A Cterminal region of Tax1BP1 bound to an intracellular domain of the ρ1 subunit, but not to other subunits of GABA C , GABA A or glycine receptors. Confocal laser-scanning microscopy demonstrated co-localization of Tax1BP1 and ρ1 in clusters at the cell membrane of transfected cells. Furthermore, Tax1BP1 and GABA C receptors were co-expressed in both synaptic layers of the retina, indicating that Tax1BP1 is a component of GABA C receptor-containing signal complexes.

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Function of γ-Aminobutyric Acid Receptor/Channel ρ1 Subunits In Spinal Cord

Cited by 40 publications

References 57 publications

Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons

Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Tax1-binding protein 1 is expressed in the retina and interacts with the GABAC receptor ρ1 subunit

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Function of γ-Aminobutyric Acid Receptor/Channel ρ1 Subunits In Spinal Cord

Cited by 40 publications

References 57 publications

Evidence for Inhibition Mediated by Coassembly of GABAAand GABACReceptor Subunits in Native Central Neurons

Evidence for Inhibition Mediated by Coassembly of GABAAand GABACReceptor Subunits in Native Central Neurons

Cross-talk and Co-trafficking between ρ1/GABA Receptors and ATP-gated Channels

Tax1-binding protein 1 is expressed in the retina and interacts with the GABAC receptor ρ1 subunit

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Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons

Evidence for Inhibition Mediated by Coassembly of GABA_Aand GABA_CReceptor Subunits in Native Central Neurons