Novel GABA responses from rod- driven retinal horizontal cells

Qian, Haohua; Dowling, John E.

doi:10.1038/361162a0

Cited by 252 publications

(194 citation statements)

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“…The GABA A R initiates a large, fast-onset, rapidly desensitizing chloride current, whereas the GABA C R is relatively nondesensitizing, with slow activating and deactivating kinetics (Cutting et al, 1991;Qian and Dowling, 1993;Pan and Lipton, 1995). Amin and Weiss (1994) found that GABA subunits expressed in Xenopus oocytes produced a very slow activation (half-time of 9 sec at the GABA EC 50 ) and deactivation (half-time of 12.5 sec).…”

Section: Comparing Gaba and Glycine Receptorsmentioning

confidence: 99%

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

Han

Zhang²,

Slaughter³

1997

J. Neurosci.

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Physiological and pharmacological properties of possible subtypes of the native glycine receptor were investigated in retinal neurons using whole-cell voltage-clamp techniques. Two discrete inhibitory glycine responses were identified in ganglion cells. The responses could be distinguished pharmacologically: one was sensitive to strychnine and the other to 5,7-dichlorokynurenic acid. The two responses had different kinetics: the former had a fast onset and fast desensitization, whereas the latter had a slower onset and was much more sustained. The physiological and pharmacological distinctions suggest that the responses are mediated by different receptors. These receptors transduce glycinergic synaptic signals to ganglion cells, where they serve as low-and high-pass filters, respectively, of EPSPs.Key words : glycine receptors; inhibition; strychnine; 5,7-dichlorokynurenic acid; ganglion cells; retina In the vertebrate retina, glycine and GABA share the task of mediating inhibition to ganglion cells. They contribute to the formation of trigger features, such as directional selectivity and edge detection (Caldwell et al., 1978). Several GABA receptor subtypes have been identified and linked to specific aspects of visual information processing Pan and Slaughter, 1991;Zhang and Slaughter, 1995). Although GABAergic and glycinergic neurons are equally populous in the inner retina, a similar diversity of glycinergic receptors has not been described.There is reason to suspect that discrete glycine receptor subtypes exist in retina. Like the GABA receptor, the glycine receptor is a pentamer of ␣ and ␤ subunits in which there are multiple isoforms. In mammalian retina, three ␣ subunit isoforms (␣ 1 , ␣ 2 , ␣ 3 ) have been localized to rat ganglion cells (Greferath et al., 1994). This molecular diversity implies functional and pharmacological variability (Becker, et al., 1988;Betz, 1991;Malosio, 1991a); however, it has proven difficult to translate molecular studies to properties of native glycine receptors or to determine the physiological significance of differential expression.We examined native glycine receptors in isolated amphibian retinal neurons and found that glycine produced two currents: a large, fast, transient, desensitizing component and a smaller, slower, sustained component. Selective antagonists of each of these two currents were identified, implicating two subtypes of the glycine receptor. The agonist and antagonist sensitivities of these two putative receptors were characterized, and their role in synaptic transmission was identified. The results indicate that tonic and phasic glycinergic IPSPs result from two populations of receptor. MATERIALS AND METHODSAnimal experimental preparation. The isolated retinal cell preparation has been described (Bader et al., 1979;Pan and Slaughter, 1995). Briefly, the tiger salamander Ambystoma tigrinum (Kons Scientific, Germantown, WI) was decapitated and pithed, and the eyes were removed. The retina was isolated and incubated for ϳ30 -60 min at room temperature (22...

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Section: Comparing Gaba and Glycine Receptorsmentioning

confidence: 99%

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

Han

Zhang²,

Slaughter³

1997

J. Neurosci.

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“…The 1 receptor subunit was cloned from a retinal library (Cutting et al, 1991), and recombinant subunits exhibited GABA C properties (Zhang et al, 1995;Qian et al, 1997). Because responses in retina to GABA were highly similar to activation of these recombinant receptors, they were attributed to GABA C receptors (Feigenspan et al, 1993;Qian and Dowling, 1993;Zhang et al, 2001).…”

Section: Introductionmentioning

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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“…The electrical responses to GABA, which have been recorded from various types of retinal cells, are due to activation of both GABA A and GABA C receptors (10)(11)(12)(13)(14), and, except for a bicuculline-resistant GABA current seen in the golden perch retina (15), all other GABA C responses desensitize very slowly. For example, the GABA currents elicited in oocytes expressing GABA1 or its alternative spliced form (GABA1⌬51) decay only about 8% or less even after 10 min of exposure to GABA (4).…”

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confidence: 99%

GABArho 1/GABAAalpha 1 receptor chimeras to study receptor desensitization

Martı́nez-Torres

Demuro²,

Miledi³

2000

Proceedings of the National Academy of Sciences

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␥-Aminobutyrate type C (GABAC) receptors are ligand-gated ion channels that are expressed preponderantly in the vertebrate retina and are characterized, among other things, by a very low rate of desensitization and resistance to the specific GABAA antagonist bicuculline. To examine which structural elements determine the nondesensitizing character of the human homomeric 1 receptor, we used a combination of gene chimeras and electrophysiology of receptors expressed in Xenopus oocytes. Two chimeric genes were constructed, made up of portions of the 1-subunit and of the ␣1-subunit of the GABAA receptor. When expressed in Xenopus oocytes, one chimeric gene (1͞␣1) formed functional homooligomeric receptors that were fully resistant to bicuculline and were blocked by the specific GABAC antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid and by zinc. Moreover, these chimeric receptors had a fast-desensitizing component, even faster than that of heterooligomeric GABAA receptors, in striking contrast to the almost nil desensitization of wild-type 1 (wt 1) receptors. To see whether the fast-desensitizing characteristic of the chimera was determined by the amino acids forming the ion channels, we replaced the second transmembrane segment (TM2) of 1 by that of the ␣1-subunit of GABAA. Although the ␣1-subunit forms fast-desensitizing receptors when coexpressed with other GABA A subunits, the sole transfer of the ␣1TM2 segment to 1 was not sufficient to form desensitizing receptors. All this suggests that the slow-desensitizing trait of 1 receptors is determined by a combination of several interacting domains along the molecule.Xenopus oocytes ͉ ␥-aminobutyrate type C receptor ͉ (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid S everal years ago a new type of ␥-aminobutyrate (GABA) receptor, now called GABA C , was identified clearly by expressing retina mRNA in Xenopus oocytes (1). In sharp contrast to the previously known GABA A receptors, the GABA C receptors show very little desensitization, are not blocked by the specific GABA A receptor antagonist bicuculline, and are not modulated by pentobarbital or steroids (1-3). GABA C is now recognized as a new family of receptors of which, so far, three members have been cloned (1-3). Moreover, there is a larger diversity of GABA C receptors because of alternative splicing (4). In contrast to the heteromeric nature of GABA A receptors, which are formed by a combination of several types of subunits, the three GABA C genes form functional homomeric receptors when expressed in Xenopus oocytes (5-9).The electrical responses to GABA, which have been recorded from various types of retinal cells, are due to activation of both GABA A and GABA C receptors (10-14), and, except for a bicuculline-resistant GABA current seen in the golden perch retina (15), all other GABA C responses desensitize very slowly. For example, the GABA currents elicited in oocytes expressing GABA1 or its alternative spliced form (GABA1⌬51) decay only about 8% or less even after 10 min of exposur...

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Novel GABA responses from rod- driven retinal horizontal cells

Cited by 252 publications

References 23 publications

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

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

GABArho 1/GABAAalpha 1 receptor chimeras to study receptor desensitization

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Novel GABA responses from rod- driven retinal horizontal cells

Cited by 252 publications

References 23 publications

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

Partition of Transient and Sustained Inhibitory Glycinergic Input to Retinal Ganglion Cells

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

GABArho 1/GABAAalpha 1 receptor chimeras to study receptor desensitization

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