The overall goal of this research continues to be to define the biochemical and functional cross talk between the sympathetic nervous system, which governs the formation of cAMP and muscle relaxation, and the parasympathetic nervous system, which governs the generation of IP3-, DAG-, Ca2+, and muscle contraction. In addition, our studies on the interactions between these systems and the sensory nervous system, which governs the release of neuropeptides, and the local hormones: prostaglandin F2a, endothelin (ET), adrenomedullin (ADM), and atrial natriuretic peptide (ANP) will be continued. Prnviously, we have developed a biochemical correlate for the functional antagonism between these systems. Here, we propose to continue to elucidate the biochemical mechanisms underlying the potential sites of interactions between these signal transduction pathways in the ocular tissues (Sphincter, dilator and ciliary muscles, human ciliary muscle (HCM) cells from normal and glaucomatous eyes, and normal (CISM) and SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. To accomplish these objectives we propose to address the following specific aims:
AIM -I will investigate the cross talk between the cyclic nucleotides (cAMP, cGMP) and the activation of the phospholipase C-beta isoforms (beta1, beta2, beta3), and their physiological consequences (contraction-relaxation and Ca2+ mobilization).
AIM -II will investigate the role of PLC-gamma and tyrosine phosphorylation in the actions of PGF2a, latanoprost, ET and carbachol (CCh) on IP3 production, Ca 2+ mobilization and contraction and their regulation by the cyclic nucleotides.
AIM -III will investigate the role of mitogen-activated protein kinase (MAPK) in the actions of PGF2a, latanoprost, ET, CCh and norepinephrine (NE) on muscle contraction and their regulation by the cyclic nucleotides.
AIM -IV will investigate the molecular mechanisms underlying the effects of ANP, ET, CGRP and ADM on the guanylyl cyclase system and their interactions with the IP3- Ca2+ system in CISM-, SV-CISM-2-, and HCM cells. For many years cyclic nucleotides have been implicated in playing a mediatory role in the IOP-lowering effects of a wide variety of drugs. The mechanisms of the ocular hypotensive effects of these drugs is unclear. Cross talk between the signal transduction pathways represent an important focal point for pharmacological manipulation, the proposed studies will provide major insights into the signal transduction mechanisms mediating the actions of PGF2a, latanoprost, ET, CCh, and NE. Understanding the cross talk between these systems will yield novel information about: (a) Characteristics and functions of ocular receptors; (b) functions and mechanisms of stimulation of PLC-beta, PLC-gamma, MAP kinases and the guanylyl-and adenylyl cyclases; (c) the G proteins that activate the effector enzymes; (d) mechanistic insights into the role of tyrosine phosphorylation in smooth muscle contraction; (d) how does cAMP and cGMP lower intracellular Ca2+ and relaxes smooth muscle; and (e) the mechanism of action of latanoprost and other ophthalmic drugs which will lead to the development of more effective antiglaucoma drugs.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004171-21
Application #
6476303
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1981-09-30
Project End
2004-06-30
Budget Start
2001-12-01
Budget End
2004-06-30
Support Year
21
Fiscal Year
2002
Total Cost
$337,381
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Kaddour-Djebbar, I; Ansari, H R; Akhtar, R A et al. (2005) Species differences in the effects of prostanoids on MAP kinase phosphorylation, myosin light chain phosphorylation and contraction in bovine and cat iris sphincter smooth muscle. Prostaglandins Leukot Essent Fatty Acids 72:49-57
Ansari, Habib R; Kaddour-Djebbar, Ismail; Abdel-Latif, Ata A (2004) Involvement of Ca2+ channels in endothelin-1-induced MAP kinase phosphorylation, myosin light chain phosphorylation and contraction in rabbit iris sphincter smooth muscle. Cell Signal 16:609-19
Ansari, Habib R; Kaddour-Djebbar, Ismail; Abdel-Latif, Ata A (2004) Effects of prostaglandin F2alpha, latanoprost and carbachol on phosphoinositide turnover, MAP kinases, myosin light chain phosphorylation and contraction and functional existence and expression of FP receptors in bovine iris sphincter. Exp Eye Res 78:285-96
Sharif, Naj A; Crider, Julie Y; Husain, Shahid et al. (2003) Human ciliary muscle cell responses to FP-class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation. J Ocul Pharmacol Ther 19:437-55
Ansari, Habib R; Davis, Angela M; Kaddour-Djebbar, Ismail et al. (2003) Effects of prostaglandin F2alpha and latanoprost on phosphoinositide turnover, myosin light chain phosphorylation and contraction in cat iris sphincter. J Ocul Pharmacol Ther 19:217-31
Husain, Shahid; Kaddour-Djebbar, Ismail; Abdel-Latif, Ata A (2002) Alterations in arachidonic acid release and phospholipase C-beta(1) expression in glaucomatous human ciliary muscle cells. Invest Ophthalmol Vis Sci 43:1127-34
Ansari, H R; Husain, S; Abdel-Latif, A A (2001) Activation of p42/p44 mitogen-activated protein kinase and contraction by prostaglandin F2alpha, ionomycin, and thapsigargin in cat iris sphincter smooth muscle: inhibition by PD98059, KN-93, and isoproterenol. J Pharmacol Exp Ther 299:178-86
Abdel-Latif, A A (2001) Cross talk between cyclic nucleotides and polyphosphoinositide hydrolysis, protein kinases, and contraction in smooth muscle. Exp Biol Med (Maywood) 226:153-63
Husain, S; Abdel-Latif, A A (2001) Effects of prostaglandin F(2alpha)and carbachol on MAP kinases, cytosolic phospholipase A(2)and arachidonic acid release in cat iris sphincter smooth muscle cells. Exp Eye Res 72:581-90
Ali, N; Yousufzai, S Y; Abdel-Latif, A A (2000) Activation of particulate guanylate cyclase by adrenomedullin in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. Cell Signal 12:491-8

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