Biomedical subjects

Shai Gavi

Publications and source records attributed to Shai Gavi.

6 recordsLinked to original sources

PubMed2006

G-protein-coupled receptors and tyrosine kinases: crossroads in cell signaling and regulation.

G-protein-coupled receptors and protein tyrosine kinases represent two prominent pathways for cellular signaling. As our knowledge of cell signaling pathways mediated by the superfamily of G-protein-coupled receptors and the smaller family of receptor tyrosine kinases expands, so does our appreciation of how these two major signaling platforms share information and modulate each other, otherwise termed "cross-talk". Cross-talk between G-protein-coupled receptors and tyrosine kinases can occur at several levels, including the receptor-to-receptor level, and at crucial downstream points (e.g. phosphatidylinositol-3-kinase, Akt/protein kinase B and the mitogen-activated protein kinase cascade). Regulation of G-protein-coupled receptors by non-receptor tyrosine kinases, such as Src family members, also operates in signaling. A broader understanding of how G-protein-coupled receptors and tyrosine kinases cross-talk reveals new insights into signaling modalities in both health and disease.

Animals↗

PubMed2005

Successful expression of a functional yeast G-protein-coupled receptor (Ste2) in mammalian cells.

G-protein-coupled receptors (GPCRs) are membrane-embedded cell signaling devices transducing ligand binding to activation of heterotrimeric G-proteins, providing a paradigm for signaling for yeast and mammals alike. Probing the extent to which yeast GPCRs may couple to mammalian G-proteins has been problematic. In the current work, we explored conditions that enable the cell-surface expression of a yeast alpha-factor pheromone receptor (Ste2). When expressed in human HEK293 cells, Ste2 is shown to bind its ligand alpha-factor, to be functional and catalyze activation of the mitogen-activated protein kinase cascade, and to demonstrate agonist-induced internalization. In response to agonist Ste2 as maintained intracellularly for several hours and avoids the degradation process observed for Ste2 in yeast cells. This is the first successful demonstration of the ability to express a functional yeast GPCR in mammalian cells.

Animals↗

PubMed2004

The 15-amino acid motif of the C terminus of the beta2-adrenergic receptor is sufficient to confer insulin-stimulated counterregulation to the beta1-adrenergic receptor.

Insulin counterregulates catecholamine action in part by inducing the sequestration of beta2-adrenergic receptors. Although similar to agonist-induced sequestration, insulin-induced internalization of beta2-adrenergic receptors operates through a distinct and better-understood cellular pathway. The effects of insulin treatment on the function and trafficking of both beta1- and beta2-adrenergic receptors were tested. The beta2-adrenergic receptors were counterregulated and internalized in response to insulin. The beta1-adrenergic receptors, in sharp contrast, are shown to be resistant to the ability of insulin to counterregulate function and induce receptor internalization. Using chimeric receptors composed of beta1-/beta2-adrenergic receptors in tandem with mutagenesis, we explored the role of the C-terminal cytoplasmic tail of the beta2-adrenergic receptors for insulin-induced counterregulation. Substitution of the C-terminal cytoplasmic tail of the beta2-adrenergic receptor on the beta1-adrenergic receptor enabled the chimeric G protein-coupled receptor to be functionally and spatially regulated by insulin. Truncation of the beta2-adrenergic receptor C-terminal cytoplasmic tail to a 15-amino acid motif harboring a potential Src homology 2-binding domain at Y350 and an Akt phosphorylation site at S345,346 was sufficient to enable receptor regulation by insulin.

Adrenergic beta-Agonists↗

PubMed2004

Adverse events due to discontinuations in drug use and dose changes in patients transferred between acute and long-term care facilities.

BACKGROUND: Care transitions are commonplace for ill older adults, but no studies to our knowledge have examined the occurrence of iatrogenic harm from medication changes during patient transfer. OBJECTIVES: To identify medication changes during transfer between hospital and nursing home and adverse drug events (ADEs) caused by these changes. METHODS: Participants were residents of 4 nursing homes in the New York City metropolitan area admitted to 2 academic hospitals. Nursing home and hospital medical records were reviewed to identify changes in medication regimens between sites. Medications were matched and compared regarding dosage, route, and frequency of administration. Two physician investigators used structured implicit review to identify ADEs attributable to transfer-related medication changes. RESULTS: During a total of 122 admissions, the mean numbers of medications altered during transfer from nursing home to hospital and hospital to nursing home were 3.1 and 1.4, respectively (P<.001 for comparison). Most changes in drug use were discontinuations, followed by dose changes and class substitutions. Of 71 bidirectional transfers that were reviewed by 2 physician investigators, ADEs attributable to medication changes occurred during 14 (20%). The overall risk of ADE per drug alteration (n = 320) was 4.4% (95% confidence interval, 2.5%-7.4%). Although most medication changes (8/14) implicated in causing ADEs occurred in the hospital, most ADEs (12/14) occurred in the nursing home after nursing home readmission. CONCLUSIONS: Medication changes are common during transfer between hospital and nursing home and are a cause of ADEs. Research is needed on interinstitutional patient care and systems interventions designed to prevent ADEs.

Adverse Drug Reaction Reporting Systems↗

PubMed2004

Trafficking of beta2-adrenergic receptors: insulin and beta-agonists regulate internalization by distinct cytoskeletal pathways.

Insulin and beta-adrenergic agonists stimulate a rapid phosphorylation and sequestration of the beta2-adrenergic receptors (beta2ARs). Although the expectation was that a common pathway would be involved in the trafficking of the beta2AR in response to either hormone, studies reported herein show the existence of unique cytoskeletal requirements for internalization/recycling of G-protein-coupled receptors, such as the beta2AR. Treatment of human epidermoid carcinoma A431 cells with nocodazole, which binds tubulin monomer in vivo and catalyzes the depolymerization of microtubules, effectively blocks beta-adrenergic agonist-induced, but not insulin-induced, sequestration of beta2ARs. Treatment with latrunculin-A, an agent that sequesters actin monomer and leads to loss of actin filaments, had no effect on the ability of beta-adrenergic agonists to stimulate internalization of beta2ARs, but blocked the ability of insulin to stimulate counterregulation of beta2ARs via internalization. Although nocodazole had no effect on insulin-stimulated sequestration of beta2ARs, the recycling of the internalized receptors to the cell membrane was sensitive to depolymerization of microtubules by this agent. Latrunculin-A, by contrast, blocks the recycling of beta2ARs internalized in response to beta-agonist, while attenuating recycling of receptors internalized in response to insulin stimulation. These data show the existence of unique cytoskeletal requirements for G-protein-coupled-receptor trafficking in response to agonist compared with a counterregulatory hormone, and for sequestration versus recycling of the receptors to the cell membrane.

Adrenergic beta-Agonists↗

PubMed2004

Probing receptor structure/function with chimeric G-protein-coupled receptors.

Owing its name to an image borrowed from Greek mythology, a chimera is seen to represent a new entity created as a composite from existing creatures or, in this case, molecules. Making use of various combinations of three basic domains of the receptors (i.e., exofacial, transmembrane, and cytoplasmic segments) that couple agonist binding into activation of effectors through heterotrimeric G-proteins, molecular pharmacology has probed the basic organization, structure/function relationships of this superfamily of heptahelical receptors. Chimeric G-protein-coupled receptors obviate the need for a particular agonist ligand when the ligand is resistant to purification or, in the case of orphan receptors, is not known. Chimeric receptors created from distant members of the heptahelical receptors enable new strategies in understanding how these receptors transduce agonist binding into receptor activation and may be able to offer insights into the evolution of G-protein-coupled receptors from yeast to humans.

Animals↗