Two Metabotropic g -Aminobutyric Acid Receptors Differentially Modulate Calcium Currents in Retinal Ganglion Cells

نویسندگان

  • Jian Zhang
  • Wen Shen
  • Malcolm M. Slaughter
چکیده

Metabotropic g -aminobutyric acid (GABA) receptors were studied in amphibian retinal ganglion cells using whole cell current and voltage clamp techniques. The aim was to identify the types of receptor present and their mechanisms of action and modulation. Previous results indicated that ganglion cells possess two ionotropic GABA receptors: GABA A R and GABA C R. This study demonstrates that they also possess two types of metabotropic GABA B receptor: one sensitive to baclofen and another to cis -aminocrotonic acid (CACA). The effects of these selective agonists were blocked by GDPb -S. Baclofen suppressed an v -conotoxin–GVIA-sensitive barium current, and this action was reversed by prepulse facilitation, indicative of a direct G-protein pathway. The effect of baclofen was also partially occluded by agents that influence the protein kinase A (PKA) pathway. But the effect of PKA activation was unaffected by prepulse facilitation, indicating PKA acted through a parallel pathway. Calmodulin antagonists reduced the action of baclofen, whereas inhibitors of calmodulin phosphatase enhanced it. Antagonists of internal calcium release, such as heparin and ruthenium red, did not affect the baclofen response. Thus, the baclofen-sensitive receptor may respond to influx of calcium. The CACA-sensitive GABA receptor reduced current through dihydropyridine-sensitive channels. Sodium nitroprusside and 8-bromo-cGMP enhanced the action of CACA, indicating that a nitric oxide system can up-regulate this receptor pathway. CACA-sensitive and baclofen-sensitive GABA B receptors reduced spike activity in ganglion cells. Overall, retinal ganglion cells possess four types of GABA receptor, two ionotropic and two metabotropic. Each has a unique electrogenic profile, providing a wide range of neural integration at the final stage of retinal information processing. key words: baclofen • cis -aminocrotonic acid • calcium/calmodulin • adenylate cyclase • guanylate cyclase i n t r o d u c t i o n The retina has emerged as a model system for the study of g -aminobutyric acid (GABA) 1 receptors. It possesses a diversity of GABA A receptors (GABA A R) (Greferath et al., 1995), at least two types of GABA B receptor (GABA B R) (Matthews et al., 1994; Tian and Slaughter, 1994), and a GABA C receptor (GABA C R) (Cutting et al., 1991). These receptors produce a variety of electrogenic effects including the ionotropic increase in chloride conductance and the metabotropic modulation of a calcium conductance and activation of a putative potassium conductance. The ability of GABA to produce this multiplicity of effects permits a precise and varied integration of synaptic information. While a plethora of GABA receptors have been identified in retina, often they have been discretely localized to small groups of neurons. For example, in white perch retina the GABA C R has been described in a roddriven horizontal cell (H4) (Qian and Dowling, 1993), while in catfish retina this receptor was found in conedriven, but not rod-driven, horizontal cells (Dong et al., 1994; Takahashi et al., 1994). The baclofen-sensitive GABA B R has been identified in fish ganglion cells but was not seen in fish horizontal or bipolar cells (Bindokas and Ishida, 1991). In one type of goldfish bipolar cell a cis -aminocrotonic acid (CACA)-sensitive, but not the baclofen-sensitive, GABA receptor was detected (Matthews et al., 1994). This restricted expression fits a model in which GABARs are precisely localized so that each receptor subtype is associated with particular neurons. The implication is that there is a functional correlation between receptor properties, such as conductance and kinetics, and the physiology of the neuron. In this context, Pan and Lipton (1995) reported that the GABA C R found in rat bipolar cells produced a smaller and slower current than the GABA A R. It is tempting to conclude that there is a good match between this receptor and the relatively slow and small responses of the rod pathway. An alternative model of GABA receptor diversity is that multiple GABARs may be localized in one cell and thereby expand the inhibitory capability of that neuDr. Jian Zhang’s present address is Department of Ophthalmology and Visual Science, University of Texas Medical Center, Houston, TX

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تاریخ انتشار 1997