Abstract

The overall objective is to understand the molecular function of the rod cGMP-gated channel. The proposal focuses on studies of the action of APT-cGMP, a photoaffinity analog of the native ligand. Three major issues are to be addressed: (1) the molecular basis for functional heterogeneity in ligand binding sites in the rod channel, specifically, whether the individual alpha and beta subunits of the native channel are subject to independent modulation; (2) how each of the multiple cGMP-binding events on a given channel contribute to activation, specifically, how open states of different conductance arise and whether the channel's beta subunit participates in activation; and (3) how specific amino acids in the channel's cGMP-binding region participate in ligand binding and activation, specifically, how C-8 substituted derivatives of cGMP that are potent channel activators interact with the cGMP binding sites.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009275-08
Application #
2711056
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Project Start
1991-08-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Kirk, Sarah R; Andrade, Adriana L; Melich, Kenneth et al. (2011) Halogen substituents on the aromatic moiety of the tetracaine scaffold improve potency of cyclic nucleotide-gated channel block. Bioorg Med Chem Lett 21:6417-9
Andrade, Adriana L; Melich, Kenneth; Whatley, G Gregory et al. (2011) Cyclic nucleotide-gated channel block by hydrolysis-resistant tetracaine derivatives. J Med Chem 54:4904-12
Strassmaier, Timothy; Kirk, Sarah R; Banerji, Tapasree et al. (2008) Block of cyclic nucleotide-gated channels by tetracaine derivatives: role of apolar interactions at two distinct locations. Bioorg Med Chem Lett 18:645-9
Strassmaier, Timothy; Karpen, Jeffrey W (2007) Novel N7- and N1-substituted cGMP derivatives are potent activators of cyclic nucleotide-gated channels. J Med Chem 50:4186-94
Rich, Thomas C; Xin, Wenkuan; Mehats, Celine et al. (2007) Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells. Am J Physiol Cell Physiol 292:C319-31
Brady, James D; Rich, Elizabeth D; Martens, Jeffrey R et al. (2006) Interplay between PIP3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A 103:15635-40
Karpen, Jeffrey W; Rich, Thomas C (2004) Resolution of cAMP signals in three-dimensional microdomains using novel, real-time sensors. Proc West Pharmacol Soc 47:1-5
Ghatpande, Ambarish S; Uma, Ramalinga; Karpen, Jeffrey W (2003) A multiply charged tetracaine derivative blocks cyclic nucleotide-gated channels at subnanomolar concentrations. Biochemistry 42:265-70
Rich, Thomas C; Karpen, Jeffrey W (2002) Review article: cyclic AMP sensors in living cells: what signals can they actually measure? Ann Biomed Eng 30:1088-99
Rich, T C; Fagan, K A; Tse, T E et al. (2001) A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. Proc Natl Acad Sci U S A 98:13049-54

Showing the most recent 10 out of 22 publications