| Polina Lishko, PhD
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The goal of my current research is to reveal how the duration of G protein signaling is regulated in photoreceptors. A cycle of G protein activation and inactivation is at the heart of process of phototransduction. Phototransduction cascade begins, when a photon of light hits a rhodopsin molecule and the energy of the photon is transformed to an onformational change of the rhodopsin. Then photoexcited rhodopsin activates multiple molecules of transducin, a photoreceptor specific member of the G protein family. Each activated transducin stimulates the activity of its effector, cGMP phosphodiesterase, which leads to a decrease in intracellular levels of cGMP. This ultimately leads to a reduction in the conductivity of ion channels on the photoreceptor plasma membrane defined as the photoresponse.
Vertebrate photoreceptors produce rapid electrical responses to light and rapidly recover from excitation upon extinction of illumination. Essential for the high speed of the photoresponse are the rates at which the G protein, transducin, is first activated by photoexcited rhodopsin and at which it is then inactivated by specific protein complex: RGS9-G5L. The rates of activation and inactivation were both documented to be at the high end of the range observed in the characterized G protein-based signaling pathways. The rapid rates of both processes may be explained, at least in part, by the membrane association of most of the signaling proteins participating in phototransduction. Membrane association may increase the probability that these proteins encounter each other in orientations optimized for their productive interactions. Photoreceptor membranes contain a limited number of specific sites responsible for the high affinity binding of RGS9-G5L. These sites could be represented by a newly discovered membrane-associated protein- R9AP (Hu G and Wensel TG. Proc Natl Acad Sci USA. 2002). Furthermore, that specific membrane association of RGS9-G5L dramatically enhances its ability to activate inactivate transducin (Lishko PV et al. J Biol Chem. 2002).
The challenge of our current experiments is to define the role of each individual protein subunit of the entire GTPase activating complex in regulating its catalytic activity and substrate specificity.
Publications
Lishko PV, Martemyanov KA, Hopp JA, Arshavsky
VY. Specific Binding of RGS9-Gbeta 5L to Protein Anchor in
Photoreceptor Membranes Greatly Enhances Its Catalytic Activity.
J Biol Chem. 2002 Jul 5;277(27):24376-81.
Kondratskaya EL, Lishko PV, Chatterjee
SS, Krishtal OA. BN52021, a platelet activating factor antagonist,
is a selective blocker of glycine-gated chloride channel.
Neurochem Int. 2002 Jun;40(7):647-53.
Piotrovskii LB, Lishko PV, Maksimyuk AP,
Aleksandrova IY, Kryshtal OA. A new class of agonists and
antagonists of N-methyl-D-aspartic acid receptors: derivatives
of imidazole-4,5- and pyrazole-3,4-dicarboxylic acids. Neurosci
Behav Physiol. 2000 Sep-Oct;30(5):553-8.
Chatterjee S, Filippov V, Lishko P, Maximyuk
O, Noldner M, Krishtal O. Hyperforin attenuates various ionic
conductance mechanisms in the isolated hippocampal neurons
of rat. Life Sci. 1999;65(22):2395-405.
Lishko PV, Maximyuk OP, Chatterjee SS,
Noldner M, Krishtal OA. The putative cognitive enhancer KA-672.HCl
is an uncompetitive voltage-dependent NMDA receptor antagonist.
Neuroreport. 1998 Dec 21;9(18):4193-7.
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