Abstract: Disclosed are methods for preventing or treating a gastrointestinal (GI) disorder in a mammal such as a human patient. In one embodiment, the methods include administering to the mammal a therapeutically effective amount of a compound that modulates a nitric oxide (NO) signaling pathway, particularly in GI neurons. Methods of the invention are particularly useful for the treatment (including prophylactic treatment) of diabetic gastropathies and other GI disorders.

Abstract: This invention relates to the method of using neurotrophic cyclophilin inhibitor compounds having an affinity for cyclophilin-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.

Abstract: Many of the effects of nitric oxide are mediated by the direct modification of cysteine residues resulting in an adduct called a nitrosothiol. A method to detect proteins which contain nitrosothiols involves several steps. Nitrosylated cysteines are converted to tagged cysteines. Tagged proteins can then be detected, for example, by immunoblotting and/or can be purified by affinity chromatography. The method is applicable to the detection of S-nitrosylated proteins in cell lysates following in vitro S-nitrosylation, as well as to the detection of endogenous S-nitrosothiols in selected protein substrates.

Abstract: Immunophilin-binding agents inhibit the phosphatase calcineurin, leading to the increased phosphorylation of certain brain proteins, including nitric oxide synthase. The increased levels of phosphorylation of nitric oxide synthase inhibits the enzymatic production of nitric oxide. Thus the neurotoxic effects of glutamate, which are ordinarily the result of vascular strokes and other neurodegenerative diseases, are minimized, because the neurotoxic effects are at least partially mediated by nitric oxide. Thus immunophilin-binding drugs can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.

Abstract: An nNOS associated protein designated PIN-1 (Protein Inhibitor of nNOS) has been identified. It physically interacts with nNOS and inhibits its activity. Multiple lines of evidence indicate that PIN-1 is a regulator of nNOS: it is physiologically associated with nNOS, and it inhibits its catalytic activity. The extraordinary evolutionary conservation of PIN-1 and preliminary evidence that it interacts with multiple proteins, suggests that it may be a major biological regulatory protein influencing numerous physiological processes.

Abstract: The present invention provides a nucleic acid comprising a sequence that encodes a sperm receptor that is related to, but is different from, a receptor of the odorant receptor family. The present invention also provides a method of obtaining a nucleic acid that comprises a sequence that encodes a sperm receptor, as well as a means of using the elements of the invention in a method of contraception, a method of detecting autoimmune infertility, and a method of affecting fertility.

Abstract: Nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is important for N-methyl-D-aspartate (NMDA) receptor-dependent neurotransmitter release, neurotoxicity, and cyclic-GMP elevations. The coupling of NMDA receptor-mediated calcium influx and nNOS activation is postulated to be due to a physical coupling of the receptor and the enzyme by an intermediary adaptor protein PSD95, through a unique PDZ-PDZ domain interaction between PSD95 and nNOS. Here we report the identification of a novel nNOS associated protein, CAPON, which is highly enriched in brain and has numerous colocalizations with nNOS. CAPON interacts with the NNOS PDZ domain through its C-terminus. CAPON competes with PSD95 for interaction with nNOS, and overexpression of CAPON results in a loss of PSD95/nNOS complexes in transfected cells. CAPON influences nNOS by regulating its ability to associate with PSD95/NMDA receptor complexes.

Abstract: Proteins which specifically bind to huntingtin, the product of the Huntington's Disease locus (HD), are used in assays for screening drug candidates. These proteins, termed huntingtin associated proteins, bind to huntingtins of both normal and Huntington's Disease patients. However, the binding is stronger to the huntingtins from the patients. The strength of binding correlates with the number of glutamine repeats in the huntingtin, which itself correlates with the time of disease onset.

Abstract: Immunophilin ligands act by binding to receptor proteins, immunophilins, which in turn can bind to and regulate the Ca.sup.2+ dependent phosphatase, calcineurin, and the Ca.sup.2+ release channel, the ryanodine receptor. Immunophilin ligands have been discovered to enhance neurite outgrowth in neuronal cell systems by increasing sensitivity to neurotrophic factors. The effects of the immunophilin ligands are detected at subnanomolar concentrations indicating therapeutic application in diseases involving neural degeneration.

Abstract: An nNOS associated protein designated PIN-1 (Protein Inhibitor of nNOS) has been identified. It physically interacts with nNOS and inhibits its activity. Multiple lines of evidence indicate that PIN-1 is a regulator of nNOS: it is physiologically associated with nNOS, and it inhibits its catalytic activity. The extraordinary evolutionary conservation of PIN-1 and preliminary evidence that it interacts with multiple proteins, suggests that it may be a major biological regulatory protein influencing numerous physiological processes.

Abstract: Immunophilin ligands act by binding to receptor proteins, immunophilins, which in turn can bind to and regulate the Ca.sup.2+ dependent phosphatase, calcineurin, and the Ca.sup.2+ release channel, the ryanodine receptor. Immunophilin ligands have been discovered to enhance neurite outgrowth in neuronal cell systems by increasing sensitivity to neurotrophic factors. The effects of the immunophilin ligands are detected at subnanomolar concentrations indicating therapeutic application in diseases involving neural degeneration.

Abstract: An amiloride sensitive sodium channel (ENAC) has been localized to the epithelium of tongue, including taste tissue. This discovery provides a method of identifying substances which stimulate or block salty taste in mammals. Alternatively spliced forms have also been identified.

Abstract: The present invention is directed to a novel von Ebner's gland secreted protein, designated Ebnerin, which is formed in the ducts of von Ebner's gland and secreted into fluid bathing the taste buds contained in the taste papillae. Ebnerin has been identified by isolation of a rat cDNA encoding a novel secreted protein of 1290 amino acids.

Abstract: Inhibitors of poly(ADP-ribose) synthetase can be used to prevent neurotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors. Poly(ADP-ribose) synthetase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.

Abstract: The present invention provides the art with methods for enhancing the sense of smell. The method involves application of an inhibitor of phosphodiesterase to the olfactory epithelium. New inhibitors can be screened using one or more phosphodiesterases isolated from olfactory mucosa. Nebulizers for applying inhibitors to the olfactory mucosa are also provided.

Abstract: Methods and devices are taught for regulating penile erection and urethral function. Inhibitors of nitric oxide synthase and precursors of nitric oxide are applied to relax or contract the muscles of the corpus cavernosum and the urethra.

Abstract: Primary cultures of purified olfactory neurons can be stimulated with physiological levels of odorants. The neurons of the cultures express markers characteristic of mature olfactory neurons in vivo, such as vimentin, olfactory marker protein and neuron-specific enolase. The cultures are useful for screening for odorants and antagonists, as well as for biochemical and physiological studies of olfactory transduction. The olfactory neurons may comprise at least about 85% of cells in the culture. The olfactory neurons demonstrate responsiveness in culture to IBMP, citraliva, and isovaleric acid.

Abstract: A method of producing primary cultures of olfactory neurons which are purified from sustentacular cells and basal cells. The neuronal cells demonstrate responsiveness to physiologic levels of odorants and express Olfactory Marker Protein (OMP). The steps required to obtain the primary cultures are:1. providing olfactory epithelium of an animal;2. dissociation of neuronal cells using enzymatic digestion;3. filtering using a mesh filter having a pore size between 10 and 25 microns to separate cell aggregates;4. removal of the cell aggregates; and5. plating the dissociated neuronal cells in a nutrient medium containing D-valine, Nerve Growth Factor (NGF), and other significant ingredients to obtain a culture of olfactory neurons. In addition to OMP the neurons are capable of expressing vimentin, neuron-specific enolase but not expressing glial fibrillary acidic proteins, S-100 protein, keratin, or neurofilament protein.

Abstract: A method of purifying calmodulin-dependent nitric oxide synthase provides a homogeneous preparation of the enzyme. The enzyme is used to raise antibodies which are a useful immunohistochemical reagent. The antibodies localize calmodulin-dependent nitric oxide synthase to a number of anatomical sites, including retina, intestine, adrenal gland, and vasculature. However, activated macrophages, which are known to possess a nitric oxide producing activity, do not display an immunoreactive protein of appropriate size on Western blots using the antibodies. Nucleotide sequences encoding calmodulin-dependent nitric oxide synthase indicate a novel sequence with a flavin binding site consensus sequence.

Abstract: Inhibitors of poly(ADP-ribose) synthetase can be used to prevent neurotoxicity mediated through N-methyl-D-aspartate (NMDA) receptors. Poly(ADP-ribose) synthetase inhibitors can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.