In many endocrine cells and most neurons, bioactive peptides are stored in large dense core vesicles (LDCVs) until release is triggered by an appropriate stimulus. Peptidylglycine alpha-amidating monooxygenase (PAM), a peptide biosynthetic enzyme, is found in nearly all cells with LDCVs and is one of the few peptide processing enzymes that spans the granule membrane. The overall goal of this research proposal is to investigate the role of Peptidylglycine alpha-Amidating Monooxygenase (PAM), a peptide biosynthetic enzyme, in signaling the cytoskeletal rearrangement required for secretion of peptides from large dense core vesicles (LDCVs), and to probe the potential for PAM to act as a transmembrane receptor, communicating the status of the LDCV lumenal milieu to relevant cytosolic factors. This will be investigated using a streptolysin-O permeabilized cell model to identify second messengers and/or PAM interactor proteins which stimulate this signaling event within the cytoplasm. The involvement of Kalirin, a recently identified PAM cytosolic domain interactor protein with GDP/GTP exchange factor activity, will be characterized using this permeabilized cell system. Further, chimeric PAM proteins will be used to screen granule components for ligands that may potentiate cytoskeletal rearrangement from within the granule lumen through a specific interaction with PAM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK009942-01
Application #
2862812
Study Section
Endocrinology Study Section (END)
Program Officer
Hyde, James F
Project Start
1999-03-16
Project End
Budget Start
1999-03-16
Budget End
2000-02-15
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Bell-Parikh, L Chastine; Ide, Tomomi; Lawson, John A et al. (2003) Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J Clin Invest 112:945-55