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Characterization of an Extended Glutamate Receptor of the on Bipolar Neuron in the Vertebrate Retina'

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Characterization of an Extended Glutamate Receptor of the on Bipolar Neuron in the Vertebrate Retina' 0270-6474/&35/0501-0224$02.00/O The Journal of Neuroscience Copyright 0 Society for Neuroscience Vol. 5, No. 1, pp. 224-233 Printed in U.S.A. January 1985 CHARACTERIZATION OF AN EXTENDED GLUTAMATE RECEPTOR OF THE ON BIPOLAR NEURON IN THE VERTEBRATE RETINA’ MALCOLM M. SLAUGHTER2 AND ROBERT F. MILLER Departments of Ophthalmology, Physiology, and Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110 Received April 11, 1984; Revised June 25, 1984; Accepted June 29, 1984 Abstract The synaptic receptors of ON bipolar neurons are selectively activated by 2-amino-4-phosphonobutyrate, a glutamate analogue. This agent uniquely distinguishes these receptors from other types of excitatory amino acid receptors found in the retina. Various glutamate and aspartate analogues were used to assess the structure- activity characteristics of this receptor. The results suggest that it represents one class of glutamate receptor which can be distinguished by its preferential activation by acidic amino acid analogues that match the extended conformation of glutamate. A decade ago, Murakami et al. (1972, 1975) demonstrated glutamate analogue, 2-amino-4-phosphonobutyrate (APB), se- that aspartate and glutamate mimicked the actions of the lectively activates only the ON bipolar receptors when applied photoreceptor neurotransmitter in the fish retina. This finding at micromolar concentrations (Slaughter and Miller, 1981). has been generalized to other vertebrate retinas and amplified Although excitatory amino acid receptors are present on most upon in the fish. Neurotransmission at this junction is partic- neurons in both the inner and outer retina (Slaughter and ularly interesting because single photoreceptors provide input Miller, 1983a), APBs direct action is limited to the ON bipolar to several classes of neurons, and evidence from our laboratory synapse. This selectivity of one glutamate analogue, in a retina indicates that each class of second-order neuron possesses a that contains many types of glutamate-sensitive neurons, sug- distinct type of acidic amino acid receptor (Slaughter et al., gests that the ON bipolar synaptic receptor represents a distinct 1983). This synaptic arrangement, in which one presynaptic class of excitatory amino acid receptor. neurotransmitter interacts with several postsynaptic receptor Based on these observations we were interested in further subtypes, is akin to that described for acetylcholine receptors characterizing the ON bipolar receptor by testing molecular in the pleural ganglion of Aplysia (Kehoe, 1967, 1969) and conformations and substitutions of glutamate that produced a rabbit superior cervical sympathetic ganglion (Libet, 1979), and selective activation of these neurons. We were aided in this it offers an opportunity to compare the pharmacology of the effort by the synaptic arrangement of the distal retina which receptor subtypes. permitted a comparison of the pharmacology of the ON bipolar We have begun to explore differences in acidic amino acid with that of the OFF bipolar and the horizontal cell. This receptors in the mudpuppy retina which, like other vertebrates, enabled us to find agents that discriminated between the three has photoreceptors that synapse on three classes of second- synaptic glutamate receptors found at one anatomical locus. order neurons: ON bipolars, OFF bipolars, and horizontal cells The molecular analysis used in this study relied on the three- (Dowling and Werblin, 1969; Werblin and Dowling, 1969; Ka- point binding of excitatory amino acids to their receptors which neko, 1970). The synaptic physiology of the photoreceptor to was established by the pioneering studies of Curtis and Watkins ON bipolar connection is unusual, and this is reflected in the (1960). They demonstrated that the activity of acidic amino synaptic pharmacology as well. A dark-released photoreceptor acids depended upon three groups: one amino and two carboxyl neurotransmitter depolarizes OFF bipolars and horizontal cells moieties. The subsequent development of both agonists and by opening channels, but apparently the same neurotransmitter antagonists has relied on the alteration of the distance between hyperpolarizes the ON bipolars by closing ionic channels (Nel- these groups or on substitutions for these charged moieties. We son, 1973; Toyoda, 1973; Werblin, 1979) Glutamate is hypoth- used a similar approach to discern the three-dimensional ar- esized to be the cone transmitter onto all second-order neurons rangement of these binding sites at the ON bipolar receptor. in the mudpuppy retina (Slaughter and Miller, 1983a). One We found that the uniqueness of this excitatory amino acid receptor could be explained by its preferential binding to lj- gands which had an intercarboxyl distance that exceeded 4 A. 1 We wish to thank Drs. G. Marshall, H. McLennan, P. Krogsgaard- These results reveal one type of excitatory amino acid receptor, Larsen, and J. C. Watkins for generously donating excitatory amino identified by APB, which can be described as an “extended” acid analogues. This work was supported by National Eye Institute glutamate receptor. Grants ROl EY 05085 and ROl EY 03014. * To whom correspondence should be sent, at his present address: Materials and Methods Department of Biophysical Sciences, 118 Cary Hall, State University Experiments were performed in the superfused retina-eyecup prep- of New York at Buffalo, Buffalo, NY 14214. aration of the mudpuppy, Necturus maculosus, using standard electro- 224 The Journal of Neuroscience ON Bipolar Glutamate Receptors 225 physiological techniques. The animals were decapitated and pithed 1mM APB before the eye, and the surrounding tissue was removed from the skull. The retina was exposed by excising the cornea, iris, lens, and vitreous. The rim of the eyecup was covered with a Kimwipe, leaving only the retina exposed. This preparation rested on a wad of Ringer’s soaked cotton and was placed in a chamber inside a light-tight Faraday cage. A pipette, placed at the rim of the eyecup, was used to introduce perfusate which formed a bath in the eyecup over the retina. The perfusate consisted of a control solution of amphibian Ringer’s (111 mM NaCl, 2.5 mM KCl, 1.8 mM CaC12, 1 mM MgClz, 10 mM dextrose, and 5 mM HEPES buffered to pH 7.80) or a Ringer’s solution contain- I ing pharmacological agents. The different perfusion solutions were -O.lnA 15mV contained in a series of bottles which were connected through separate I- Teflon-lined valves and tubing to a mixing chamber. A short length of 20 set polyethylene tubing, that serves as the common exit from the mixing chamber, was fed into the perfusion pipette near the retina. The perfusates were bubbled with oxygen and the flow rate was maintained at approximately 2 ml/min. This system permitted the addition of two or more solutions to the retina simultaneously, and the exchange time on switching solutions (due to dead space in the lines) was about 15 to 25 sec. A dual-beam light bench projected focused images of a small spot (200 pm), an annulus (400 pm inner diameter; outer diameter > retinal diameter), or a diffuse light onto the retina (irradiance = 5 X 10e9/ cm*). Light responses were cone dominated under our experimental -O.lnA GO.1 nA conditions. Microelectrodes (250 to 600 megohms) were filled with 3 M potassium acetate and were advanced into the retina by a hydraulic microdrive using capacitative buzzing to facilitate cell penetration. Recordings were obtained using a Dagan model 8100 amplifier. Cellular 20mV conductance changes due to light stimuli or drug application were assessed by applying O.l-nA current pulses into the neuron through the 5 set recording electrode. Under control conditions, the voltage deflection Figure 1. APB and the photoreceptor neurotransmitter produce due to this current injection was eliminated by the bridge balance, and similar conductance changes in ON bipolar cells. In the top truce, a then the voltage deflection seen during stimulation was used to evaluate -O.l-nA current pulse is iniected into an ON bipolar cell during the changes in membrane conductance. More complete descriptions of the sustained portion-of the light response, when relatively little photore- methodology have been presented previously (Miller and Dacheux, ceptor transmitter is being released. The amplifier bridge is balanced 1976; Slaughter and Miller, 1983a). so that this current produces only a slight voltage deflection. During The n,L-2-amino-4-phosphonobutyyrate and the D,L-2-amino-3-phos- the application of APB, the light response is suppressed and the phonopropionate were obtained from Calbiochem. Dr. J. C. Watkins negative current produces a larger negative voltage deflection, indicat- kindly provided samples of D,L-2-amino-5-phosphonovalerate, c&2,3- ing an increase in the input resistance of the cell. In another ON piperidine dicarboxylic acid, and the D and L isomers of 2-amino-4- bipolar, shown in the bottom trace, both negative and positive current phosphonobutyrate (these compounds are now commercially available pulses were applied. At the first arrow, a O.l-nA negative current pulse from Cambridge Research Biochemicals). Dr. H. McLennan generously produces a negative deflection in the dark, but a positive deflection supplied a sample of cis-1,3-amino-dicarboxylcyclopentane (ADCP), during the light response indicating that the photoreceptor transmitter and Dr. G. Marshall kindly donated 4-amino-4 phosphonobutyrate. All also increases the neuron’s input resistance in the dark. At the second other compounds were purchased from Sigma Chemical Co. arrow, a positive current pulse also indicated that the cell’s input Ibotenate, a glutamate analogue that was used in this study, can resistance was greater in the dark than in the light. The duration of apparently be converted to muscimol, a GABA analogue. This reaction drug application is indicated by the bar above the voltage trace and the can occur spontaneously or due to biological decarboxylation. When timing of diffuse light stimuli is denoted by the bars below the traces. we used this compound we periodically assessed its effects on inner retinal neurons, where GABA has a very potent inhibitory action.
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