David Gurwitz | Tel Aviv University (original) (raw)
Papers by David Gurwitz
Molecular Medicine Today, 2000
Molecular Medicine Today, 2000
Trends in Molecular Medicine, 2002
Trends in Molecular Medicine, 2001
Molecular Medicine Today, 1999
Molecular Medicine Today, 1999
Molecular Medicine Today, 1999
Molecular Medicine Today, 2000
Molecular Medicine Today, 1998
ABSTRACT
Trends in Immunology, 2001
The Lancet, 1999
... References. 1 Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascula... more ... References. 1 Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy. Lancet 1998; 352: 1965-1969. ...
Journal of Biological Chemistry, 2002
High affinity choline uptake plays a critical role in the regulation of acetylcholine synthesis i... more High affinity choline uptake plays a critical role in the regulation of acetylcholine synthesis in cholinergic neurons. Recently, we succeeded in molecular cloning of the high affinity choline transporter (CHT1), which is specifically expressed in cholinergic neurons. Here we demonstrate the presence of functionally relevant, nonsynonymous single nucleotide polymorphism in the human CHT1 gene by comprehensive sequence analysis of the exons and the intron/exon boundaries including the transcription start site. The deduced amino acid change for the polymorphism is isoleucine to valine at amino acid 89 (I89V) located within the third transmembrane domain of the protein. The allele frequency of I89V was 6% for Ashkenazi Jews. Functional assessment of the I89V transporter in mammalian cell lines revealed a 40-50% decrease in V(max) for choline uptake rate compared with the wild type, whereas there was no alteration in the apparent affinities for choline, sodium, chloride, and the specific inhibitor hemicholinum-3. There also was no change in the specific hemicholinum-3 binding activity. The decreased choline uptake was not associated with the surface expression level of the protein as assessed by biotinylation assay. These results suggest an impaired substrate translocation in the I89V transporter. The Caenorhabditis elegans ortholog of CHT1 has a valine residue at the corresponding position and a single replacement from valine to isoleucine caused a decrease in the choline uptake rate by 40%, suggesting that this hydrophobic residue is generally critical in the choline transport rate in CHT1. This polymorphism in the allelic CHT1 gene may represent a predisposing factor for cholinergic dysfunction.
Expert Opinion on Investigational Drugs, 1999
Transdermal nicotine patches have been successfully introduced as a safe and powerful aid to smok... more Transdermal nicotine patches have been successfully introduced as a safe and powerful aid to smoking cessation; this has contributed to the rising interest in additional therapeutic applications for nicotine and synthetic nicotinic agonists. Nicotine and nicotinic agonists may have a therapeutic potential for a variety of disorders, including Alzheimer's and Parkinson's diseases, depression, attention deficit disorder, Tourette's syndrome and ulcerative colitis. These interests are partially fuelled by the urgent need of the tobacco industry to find new niches for nicotine in a world bound eventually to retire from cigarette smoking. At the same time, there is an increased interest in developing drugs for fighting obesity, a growing affliction of industrialised nations. This review presents data on the potential of nicotine, and in particular synthetic nicotinic agonists, for controlling body weight. Nicotinic agonists may become relatively safe, effective and inexpensive alternatives for several optional drugs currently being developed for treating human obesity, including beta-3-adrenergic agonists, leptin and its agonists, and neuropeptide Y antagonists.
Current Pharmacogenomics and Personalized Medicine, 2013
New England Journal of Medicine, 2011
![Research paper thumbnail of Recognition of the muscarinic receptor by its endogenous neurotransmitter: binding of [3H]acetylcholine and its modulation by transition metal ions and guanine nucleotides](https://attachments.academia-assets.com/41709296/thumbnails/1.jpg)
](Proceedings of the National Academy of Sciences, 1984
Agonist binding to the muscarinic receptor in rat cerebral cortex membranes was studied by using ... more Agonist binding to the muscarinic receptor in rat cerebral cortex membranes was studied by using the neurotransmitter itself, [3H]acetylcholine ([3H]AcCho). By using 10 !LM atropine or oxotremorine to define specific binding, it
Biochemistry, 1985
Tetranitromethane (TNM) modifies the muscarinic receptors from rat cerebral cortex. The modified ... more Tetranitromethane (TNM) modifies the muscarinic receptors from rat cerebral cortex. The modified receptor possesses an increased binding affinity (6-9-fold) toward several agonists such as acetylcholine, carbamoylcholine, arecoline, etc. The binding of antagonists (Bmax and Kd) is only slightly altered. The effects of TNM treatment can be prevented by atropine, thus indicating that TNM modifies residue(s) at the binding site. We carried out a series of successive chemical modifications which indicated that the modified residue(s) is (are) most probably a tyrosyl and not a cysteinyl residue. This conclusion gains support from the pH profile of agonist binding, which suggests the involvement of a residue with an apparent pK comparable to that of the phenolic hydroxyl of a nitrotyrosyl residue. The binding properties of the modified receptor, when compared to those of the native one, clearly indicate that the response to TNM modification with respect to the binding of agonists such as acetylcholine and carbamoylcholine is different from that when oxotremorine and its analogue are employed. This is interpreted as being the result of different binding modes exhibited by the various agonists. Nitration of the receptors can be prevented by the presence of an antagonist but not by an agonist. We propose that this differential response is due to the formation of ligand-receptor complexes that differ with respect to the microenvironment of the modified tyrosyl residue.
Molecular Medicine Today, 2000
Molecular Medicine Today, 2000
Trends in Molecular Medicine, 2002
Trends in Molecular Medicine, 2001
Molecular Medicine Today, 1999
Molecular Medicine Today, 1999
Molecular Medicine Today, 1999
Molecular Medicine Today, 2000
Molecular Medicine Today, 1998
ABSTRACT
Trends in Immunology, 2001
The Lancet, 1999
... References. 1 Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascula... more ... References. 1 Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy. Lancet 1998; 352: 1965-1969. ...
Journal of Biological Chemistry, 2002
High affinity choline uptake plays a critical role in the regulation of acetylcholine synthesis i... more High affinity choline uptake plays a critical role in the regulation of acetylcholine synthesis in cholinergic neurons. Recently, we succeeded in molecular cloning of the high affinity choline transporter (CHT1), which is specifically expressed in cholinergic neurons. Here we demonstrate the presence of functionally relevant, nonsynonymous single nucleotide polymorphism in the human CHT1 gene by comprehensive sequence analysis of the exons and the intron/exon boundaries including the transcription start site. The deduced amino acid change for the polymorphism is isoleucine to valine at amino acid 89 (I89V) located within the third transmembrane domain of the protein. The allele frequency of I89V was 6% for Ashkenazi Jews. Functional assessment of the I89V transporter in mammalian cell lines revealed a 40-50% decrease in V(max) for choline uptake rate compared with the wild type, whereas there was no alteration in the apparent affinities for choline, sodium, chloride, and the specific inhibitor hemicholinum-3. There also was no change in the specific hemicholinum-3 binding activity. The decreased choline uptake was not associated with the surface expression level of the protein as assessed by biotinylation assay. These results suggest an impaired substrate translocation in the I89V transporter. The Caenorhabditis elegans ortholog of CHT1 has a valine residue at the corresponding position and a single replacement from valine to isoleucine caused a decrease in the choline uptake rate by 40%, suggesting that this hydrophobic residue is generally critical in the choline transport rate in CHT1. This polymorphism in the allelic CHT1 gene may represent a predisposing factor for cholinergic dysfunction.
Expert Opinion on Investigational Drugs, 1999
Transdermal nicotine patches have been successfully introduced as a safe and powerful aid to smok... more Transdermal nicotine patches have been successfully introduced as a safe and powerful aid to smoking cessation; this has contributed to the rising interest in additional therapeutic applications for nicotine and synthetic nicotinic agonists. Nicotine and nicotinic agonists may have a therapeutic potential for a variety of disorders, including Alzheimer's and Parkinson's diseases, depression, attention deficit disorder, Tourette's syndrome and ulcerative colitis. These interests are partially fuelled by the urgent need of the tobacco industry to find new niches for nicotine in a world bound eventually to retire from cigarette smoking. At the same time, there is an increased interest in developing drugs for fighting obesity, a growing affliction of industrialised nations. This review presents data on the potential of nicotine, and in particular synthetic nicotinic agonists, for controlling body weight. Nicotinic agonists may become relatively safe, effective and inexpensive alternatives for several optional drugs currently being developed for treating human obesity, including beta-3-adrenergic agonists, leptin and its agonists, and neuropeptide Y antagonists.
Current Pharmacogenomics and Personalized Medicine, 2013
New England Journal of Medicine, 2011
Proceedings of the National Academy of Sciences, 1984
Agonist binding to the muscarinic receptor in rat cerebral cortex membranes was studied by using ... more Agonist binding to the muscarinic receptor in rat cerebral cortex membranes was studied by using the neurotransmitter itself, [3H]acetylcholine ([3H]AcCho). By using 10 !LM atropine or oxotremorine to define specific binding, it
Biochemistry, 1985
Tetranitromethane (TNM) modifies the muscarinic receptors from rat cerebral cortex. The modified ... more Tetranitromethane (TNM) modifies the muscarinic receptors from rat cerebral cortex. The modified receptor possesses an increased binding affinity (6-9-fold) toward several agonists such as acetylcholine, carbamoylcholine, arecoline, etc. The binding of antagonists (Bmax and Kd) is only slightly altered. The effects of TNM treatment can be prevented by atropine, thus indicating that TNM modifies residue(s) at the binding site. We carried out a series of successive chemical modifications which indicated that the modified residue(s) is (are) most probably a tyrosyl and not a cysteinyl residue. This conclusion gains support from the pH profile of agonist binding, which suggests the involvement of a residue with an apparent pK comparable to that of the phenolic hydroxyl of a nitrotyrosyl residue. The binding properties of the modified receptor, when compared to those of the native one, clearly indicate that the response to TNM modification with respect to the binding of agonists such as acetylcholine and carbamoylcholine is different from that when oxotremorine and its analogue are employed. This is interpreted as being the result of different binding modes exhibited by the various agonists. Nitration of the receptors can be prevented by the presence of an antagonist but not by an agonist. We propose that this differential response is due to the formation of ligand-receptor complexes that differ with respect to the microenvironment of the modified tyrosyl residue.