(-)-baclofen and gamma-aminobutyric acid inhibit calcium currents in isolated retinal ganglion cells.

Abstract

Of the various synaptic inputs known to converge upon retinal ganglion cells, the major inhibitory inputs are thought to be GABAergic. Although y-aminobutyric acid (GABA) is known to activate anion-selective ion channels in retinal ganglion cells, we have tested the possibility that GABA can also modulate cationic conductances in these cells, as seen in other central and peripheral neurons. Specifically, we have made whole-cell patch-clamp recordings to test whether voltage-gated calcium currents in isolated goldfish retinal ganglion cells are sensitive to GABAB receptor ligands. (-)-Baclofen and GABA inhibited calcium currents activated by moderately long depolarizations and, during large depolarizations (e.g., to 0 mV), also appeared to accelerate the rate of current decay. The calcium current inhibition induced by (-)-baclofen and GABA was not prevented by 2-hydroxysaclofen, phadofen, or bicuculline, even though bicuculline suppressed a GABA-activated conductance in these cells. These results demonstrate the presence of baclofen-and GABAsensitive calcium currents in vertebrate retinal ganglion cells as well as the coexistence of GABAA and GABAB receptors in individual retinal ganglion cells.The inner plexiform layer of the retina is one of the most widely studied synaptic neuropils of vertebrate central nervous system. Here, retinal ganglion cells receive excitatory and inhibitory synaptic inputs from a variety of interneurons known as bipolar and amacrine cells (see ref. 1). Of these inputs, the major inhibitory pathways appear to be GABAergic: endogenous y-aminobutyric acid (GABA), its synthetic enzyme glutamic acid decarboxylase, GABA-sequestering neuronal processes, GABAA receptor-channel complexes, and both muscimol-and benzodiazepine-binding sites are distributed throughout this plexus; GABA and glutamic acid decarboxylase have been localized in amacrine cells forming morphological synapses onto ganglion cells; and many if not all retinal ganglion cells are inhibited by exogenous GABA in various species (2-4).GABA can activate a chloride conductance in both nonmammalian and mammalian retinal ganglion cells (e.g., refs. 5-7). This may not account for all effects of GABA on these cells, however, given observations in other individual central and peripheral neurons that GABA can activate more than one type of receptor (e.g., refs. 8 and 9). The most wellknown of these are GABAB receptors, which are coupled to calcium and potassium conductances and are pharmacologically distinguishable from GABAA receptors coupled to chloride conductances (10). Recent voltage-clamp studies have shown that GABA and the GABAB receptor agonist, baclofen, inhibit calcium currents of retinal cone and bipolar cells (11, 12), while a baclofen-sensitive potassium current has been inferred on the basis of voltage recordings from proximal retinal neurons in situ (13).GABAergic modulation of calcium currents in retinal ganglion cells has not previously been demonstrated to our knowledge. However, because most (if not all) clas...

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals

“…However, our calcium imaging methods did not reveal this novel GABA,-like receptor in our preparation, since CACA was ineffective at low concentrations. We also failed to detect a baclofen-sensitive GABA, receptor in our preparation, although such a receptor has also been reported to modulate Ca2+ channels at tiger salamander bipolar cell terminals (Maguire et al, 1989) and goldfish ganglion cells (Bindokas and Ishida, 1991), and to regulate retinal signal processing (Pan and Slaughter, 1991;Slaughter and Pan, 1992). It is not clear if this discrepancy is due to species variation or methodological differences.…”

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals

“…However, our calcium imaging methods did not reveal this novel GABA,-like receptor in our preparation, since CACA was ineffective at low concentrations. We also failed to detect a baclofen-sensitive GABA, receptor in our preparation, although such a receptor has also been reported to modulate Ca2+ channels at tiger salamander bipolar cell terminals (Maguire et al, 1989) and goldfish ganglion cells (Bindokas and Ishida, 1991), and to regulate retinal signal processing (Pan and Slaughter, 1991;Slaughter and Pan, 1992). It is not clear if this discrepancy is due to species variation or methodological differences.…”

Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion

“…So we speculated that chronic hypoperfusion-induced increase in the intracellular Ca 2+ concentration could enhance the desensitization of GABA A receptors resulting in the reduction of GABA A receptors surface expression. Previous studies have reported that dose-dependent administration of baclofen depresses Ca 2+ -influx 82 83 84 . Besides, it has been demonstrated that GABA B receptors activation suppresses NMDA receptors - mediated Ca 2+ influx by attenuating the activity of Src in rat four-vessel occlusion (4-VO) ischemic model 31 .…”

Multireceptor GABAergic regulation of synaptic communication in amphibian retina

“…There is considerable evidence that GABA B receptor activation can modulate channel activity and alter light responses in ganglion cells in fish, amphibian and mammalian retinas (Bai & Slaughter, 1989; Maguire et al 1989; Ikeda et al 1990; Bindokas & Ishida, 1991; Müller et al 1992; Zhang et al 1997 b) . In amphibian retina, there is conflicting evidence on whether GABA B agonists can modulate bipolar cell presynaptic calcium channels, although the agonist baclofen has been shown to suppress synaptic communication between bipolar cells and ganglion cells (Maguire et al 1989; Slaughter & Bai, 1989; Lukasiewicz et al 1994).…”

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals

“…However, our calcium imaging methods did not reveal this novel GABA,-like receptor in our preparation, since CACA was ineffective at low concentrations. We also failed to detect a baclofen-sensitive GABA, receptor in our preparation, although such a receptor has also been reported to modulate Ca2+ channels at tiger salamander bipolar cell terminals (Maguire et al, 1989) and goldfish ganglion cells (Bindokas and Ishida, 1991), and to regulate retinal signal processing (Pan and Slaughter, 1991;Slaughter and Pan, 1992). It is not clear if this discrepancy is due to species variation or methodological differences.…”

Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion

“…So we speculated that chronic hypoperfusion-induced increase in the intracellular Ca 2+ concentration could enhance the desensitization of GABA A receptors resulting in the reduction of GABA A receptors surface expression. Previous studies have reported that dose-dependent administration of baclofen depresses Ca 2+ -influx 82 83 84 . Besides, it has been demonstrated that GABA B receptors activation suppresses NMDA receptors - mediated Ca 2+ influx by attenuating the activity of Src in rat four-vessel occlusion (4-VO) ischemic model 31 .…”

Multireceptor GABAergic regulation of synaptic communication in amphibian retina

“…There is considerable evidence that GABA B receptor activation can modulate channel activity and alter light responses in ganglion cells in fish, amphibian and mammalian retinas (Bai & Slaughter, 1989; Maguire et al 1989; Ikeda et al 1990; Bindokas & Ishida, 1991; Müller et al 1992; Zhang et al 1997 b) . In amphibian retina, there is conflicting evidence on whether GABA B agonists can modulate bipolar cell presynaptic calcium channels, although the agonist baclofen has been shown to suppress synaptic communication between bipolar cells and ganglion cells (Maguire et al 1989; Slaughter & Bai, 1989; Lukasiewicz et al 1994).…”

Multiple GABA receptor subtypes mediate inhibition of calcium influx at rat retinal bipolar cell terminals

“…However, our calcium imaging methods did not reveal this novel GABA,-like receptor in our preparation, since CACA was ineffective at low concentrations. We also failed to detect a baclofen-sensitive GABA, receptor in our preparation, although such a receptor has also been reported to modulate Ca2+ channels at tiger salamander bipolar cell terminals (Maguire et al, 1989) and goldfish ganglion cells (Bindokas and Ishida, 1991), and to regulate retinal signal processing (Pan and Slaughter, 1991;Slaughter and Pan, 1992). It is not clear if this discrepancy is due to species variation or methodological differences.…”

Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion

“…So we speculated that chronic hypoperfusion-induced increase in the intracellular Ca 2+ concentration could enhance the desensitization of GABA A receptors resulting in the reduction of GABA A receptors surface expression. Previous studies have reported that dose-dependent administration of baclofen depresses Ca 2+ -influx 82 83 84 . Besides, it has been demonstrated that GABA B receptors activation suppresses NMDA receptors - mediated Ca 2+ influx by attenuating the activity of Src in rat four-vessel occlusion (4-VO) ischemic model 31 .…”

Multireceptor GABAergic regulation of synaptic communication in amphibian retina

“…There is considerable evidence that GABA B receptor activation can modulate channel activity and alter light responses in ganglion cells in fish, amphibian and mammalian retinas (Bai & Slaughter, 1989; Maguire et al 1989; Ikeda et al 1990; Bindokas & Ishida, 1991; Müller et al 1992; Zhang et al 1997 b) . In amphibian retina, there is conflicting evidence on whether GABA B agonists can modulate bipolar cell presynaptic calcium channels, although the agonist baclofen has been shown to suppress synaptic communication between bipolar cells and ganglion cells (Maguire et al 1989; Slaughter & Bai, 1989; Lukasiewicz et al 1994).…”