Abstract

The objective of this research is to study the mechanism of signal transduction from the insulin receptor to two membrane transporters: the (Na,K)ATPase and a Na channel. The methods of protein chemistry and molecular biology will be used. The structure of the insulin receptor will be studied to determine the importance of the dimeric structure of the receptor for signal transduction; the interaction of G proteins with the receptor and the dependence of this interaction on the dimeric structure of the receptor are also questions of interest. The region in the primary structure of the alpha2 isoform of the (Na,K)ATPase that is necessary for regulation of the pump by insulin will be investigated by making hybrid alpha1/alpha2 polypeptides and by studying the molecules that interact with this region of the (Na,K)ATPase. The insulin dependent Na channel identified in skeletal muscle will be isolated, characterized, and the gene for the channel cloned and expressed; the relationship of this channel to other Na channels will be of particular interest.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027626-12
Application #
3228408
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1981-03-01
Project End
1997-02-28
Budget Start
1993-03-01
Budget End
1994-02-28
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

Wu, James Jianping; Guidotti, Guido (2004) Proreceptor dimerization is required for insulin receptor post-translational processing. J Biol Chem 279:25765-73
Wu, James Jianping; Guidotti, Guido (2002) Construction and characterization of a monomeric insulin receptor. J Biol Chem 277:27809-17
Lee, K; Jung, J; Kim, M et al. (2001) Interaction of the alpha subunit of Na,K-ATPase with cofilin. Biochem J 353:377-85
Chen, W; Guidotti, G (2001) Soluble apyrases release adp during ATP hydrolysis. Biochem Biophys Res Commun 282:90-5
Coppi, M V; Compton, L A; Guidotti, G (1999) Isoform-specific effects of charged residues at borders of the M1-M2 loop of the Na,K-ATPase alpha subunit. Biochemistry 38:2494-505
Coppi, M V; Guidotti, G (1997) The alpha2L111R,N122D isoform of the Na,K-ATPase expressed in HeLa cells does not undergo an adipocyte-like increase in activity in response to insulin. Biochem Biophys Res Commun 236:444-8
Coppi, M V; Guidotti, G (1997) Intracellular localization of Na,K-ATPase alpha2 subunit mutants. Arch Biochem Biophys 346:312-21
Coppi, M V; Guidotti, G (1997) Ubiquitination of Na,K-ATPase alpha1 and alpha2 subunits. FEBS Lett 405:281-4
Santy, L C; Guidotti, G (1997) Expression of a single gene produces both forms of skeletal muscle cyclic nucleotide-gated channels. Am J Physiol 273:E1140-8
Santy, L C; Guidotti, G (1996) Reconstitution and characterization of two forms of cyclic nucleotide-gated channels from skeletal muscle. Am J Physiol 271:E1051-60

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