Jahanshah Amin - US grants

A novel GABA receptor channel subunit (rho 1-in), highly homologous to the rho 1, has been isolated from a human retinal cDNA library using conventional screening techniques. Expression of this isoform of rho 1 yields robust homo-oligomeric receptor channels with distinct pharmacological and kinetic properties. For rho 1-in receptor channel, the GABA-induced current at low agonist concentration rose exceeding slow. Following removal of the agonist the evoked-currents decayed at a remarkably slow rate. Finally, in comparison to the rho 1, the rho 1- in receptor channel displayed higher sensitivity to GABA. These characteristics make rho 1-in receptor channel unique among all GABA- gated chloride channels examined thus far. In the retina where graded potential is the predominant form of intercommunication, rho 1-in receptor channel can respond to low GABA concentrations at which all other identified GABA receptor channels exhibit no response. And because of its uniquely slow activation/deactivation properties, rho 1-in receptor channels can operate with exceptionally long dynamic range. The goal of the proposed research is to define the molecular components underlying the unique characteristic of the rho 1-in receptor channels using molecular and electrophysiological techniques. Planned experiments address three hypotheses. 1. The subtle differences between the amino acid sequences of the rho 1-in and rho 1 dictate the unique pharmacology; activation and deactivation kinetics for rho 1-in receptor channels. 2. The rho 1-in subunit messenger RNA (mRNA) is expressed only in the retina and the relative expression of rho 1-in mRNA is less than that of rho 1 mRNA. 3. Pharmacology of the rho 1-in receptor channels with a variety of GABA agonists is distinct from that of the rho 1 receptor channels. Understanding the wiring of the retina and the coordination of on-and- off switches among their intertwined networks, is an essential step towards the elucidation of how visual processes take shape. Diverse retinal neurons network and fine tune the signal output to the brain. Neurotransmitter-gated ion channels at the synapses within this network, are the key components in regulating these signal transductions. Elucidation of the pharmacology of rho 1-in receptor channels, and the molecular basis underlying its slow activation and deactivation, not only may assist in solving a component of the retinal signal coordination and transduction jigsaw puzzle but also may shed light on the mechanism involved int he dynamics of ligand-gated receptor channels in general.