In the iris smooth muscle of the eye neurotransmitters such as acetylcholine and norepinephrine interact with muscarinic-cholinergic and Alpha 1-adrenergic receptors, respectively, to cause mobilizaiton of Ca2+, and this results in an increase in intracellular Ca2+ and consequently in muscle contraction. In addition, the neurotransmitter-receptor interaction results in a selective stimulation of the turnover of the acidic phospho-lipids which incude the polyphosphoinositides (poly PI) dicphosphoinositide (DPI) and triphosphoinositide (TPI). Since our early characterization of the neurotransmitter-induced breakdown of TPI in the iris several investigators have observed this phenomenon in a variety of tissues and it is believed now that the initial reaction in the activation of Ca2+ mobilizing receptors is the breakdown of TPI into diacylglycerol (DG) and inositol triphosphate (InP3). The underlying molecular mechanism of the enhanced TPI breakdown and its physiological consequences are still unclear. The goals of the proposed research program are to throw more light, through biochemical-pharmacological studies, on the molecular mechanism(s) underlying the interrelationships between neurotransmitter-induced TPI breakdown, Ca2+ mobilization, DG-induced protein kinase C activation and muscle contraction and lactate formation in rabbit and bovine irides. It is hoped that the findings from the proposed research program will extent our understanding of the physiological role and relative positions of Ca2+ and poly PI in the sequence of biochemical events that link receptor activation to smooth muscle response. Furthermore, because the phosphoinositide turnover is a universal biochemical event, our findings, as in the past, will undoubtedly apply to a variety of tissues. Finally, our proposed studies will, hopefully, throw more light on the following: (a) Yield relevant information with regard to the mechanism and function of muscarinic and Alpha 1-adrenergic receptors in smooth muscles of the eye. (b) Nature of the involvement of phospholipids and phosphoproteins in neurotransmitter-induced membrane permeability, and illumination of the phosphate rearrangement in regulation of membrane permeability during receptor activation. (c) Mechanism of action of pharmacological agents in the eye. (d) Mechanism of aqueous humor formation, which is involved in regulating intraocular pressure. (e) Mechanistic insights into the biochemistry, pharmacology, and physiology of the iris smooth muscle.
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