The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)
signal transduction pathway plays a role in every retinal cell type.
Previous studies have shown that excitatory glutamatergic synaptic
pathways can increase cGMP-like immunoreactivity (cGMP-LI) in retina
through stimulation of NO production, but little is known about the
role of synaptic inhibition in the modulation of cGMP-LI.
Gamma-amino-n-butyric acid (GABA) plays critical roles in modulating
excitatory synaptic pathways in the retina. Therefore, we used GABA
receptor antagonists to explore the role of GABAergic inhibitory
synaptic pathways on the modulation of the NO/cGMP
signal-transduction system. Cyclic GMP immunocytochemistry was used to
investigate the effects of the GABA receptor antagonists bicuculline,
picrotoxin, and (1,2,5,6-tetrahyropyridin-4-yl) methylphosphinic acid
(TPMPA) on levels of cGMP-LI. Cyclic GMP-LI was strongly increased in
response to the GABAA receptor antagonist bicuculline, while
the GABAC receptor antagonist TPMPA had little effect on
cGMP-LI. The GABAA/GABAC receptor antagonist,
picrotoxin, caused a moderate increase in cGMP-LI, which was mimicked
by the combination of bicuculline and TPMPA. The nitric oxide synthase
inhibitor, S-methyl-L-thiocitrulline (SMTC), blocked the increased
cGMP-LI in response to stimulation with either bicuculline or
picrotoxin. Treatments with either of the glutamate receptor
(MK-801) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) partially
blocked the increases in cGMP-LI seen in response to bicuculline, but a
combination of MK-801 and CNQX completely eliminated these increases.
These results suggest that inhibitory synaptic pathways involving both
types of GABA receptors work through excitatory glutamatergic receptors
to regulate the NO/cGMP signal-transduction pathway in retina.