The overall objective is to study the mechanisms underlying the activation and regulation of key metabolic processes in the neonate, viz hepatic gluconeogenesis, glycogenolysis and fat metabolism. This activation, in part, involves events mediated at the cell surface by hormones linked to the adenylate cyclase system. Modulation of this enzyme by hormones involves interactions among three plasma membrane proteins: viz, the receptor, a guanine necleotide-sensitive component (dubbed G- or N- protein), and C, the catalytic component of the cyclase. In addition, there are at least two specific effectors, the hormone and GTP. The project is a systematic study of the ontogeny and functional integration of the three components of hepatic adenylate cyclase system during neonatal development, and the relationship of these changes to overall control of hepatic glucose output in the neonate. The long-term goals include studies to understand the long-term regulation of the adenylate cyclase system and the regulation of the developmental expression of key components of the system.
The specific aims for this project period are i) to study the potential role of inhibitory components in this system in the hormonal responsiveness of the neonatal hepatocyte so as to understand whether the subsensitivity of the neonatal hepatocyte to hormonal stimulation may be a result of endogenous inhibition of the cyclase system; ii) to measure the concentrations of the stimulatory and inhibitory components and to decipher the molecular basis for the refractoriness of adenylate cyclase during early neonatal development; iii) to study whether uncoupling of, for example, the Beta-receptor, from the regulatory unit results from or is causally related to possible phosphorylation of the receptor and/or alterations in the subunits of N. These studies should be valuable in understanding molecular mechanisms underlying neonatal hypoglycemia and the problem of tissue refractoriness to hormones which is a frequently encountered phenomenon, e.g., in tissues of diabetic persons or in abnormal development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD008792-15
Application #
3310997
Study Section
Metabolism Study Section (MET)
Project Start
1978-01-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
15
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Meharry Medical College
Department
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37208
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Jiang, P; Arinze, I J (1994) Developmental and glucocorticoid modulation of the expression of mRNAs for Gs alpha and G beta subunits in neonatal liver. Mol Cell Endocrinol 99:95-102
Kawai, Y; Arinze, I J (1993) Glucocorticoid regulation of G-protein subunits in neonatal liver. Mol Cell Endocrinol 90:203-9
Kawai, Y; Arinze, I J (1991) Ontogeny of guanine-nucleotide-binding regulatory proteins in rabbit liver. Biochem J 274 ( Pt 2):439-44
Graham, S M; Arinze, I J (1987) High and low affinity sites associated with the binding of [3H]guanyl-5'-yl imidodiphosphate to liver plasma membranes. Res Commun Chem Pathol Pharmacol 56:301-20
Graham, S M; Herring, P A; Arinze, I J (1987) Age-associated alterations in hepatic beta-adrenergic receptor/adenylate cyclase complex. Am J Physiol 253:E277-82
Kawai, Y; Powell, A; Arinze, I J (1986) Adrenergic receptors in human liver plasma membranes: predominance of beta 2- and alpha 1-receptor subtypes. J Clin Endocrinol Metab 62:827-32
Kawai, Y; Graham, S M; Yoshioka, H et al. (1986) Beta-adrenergic receptors in guinea-pig liver plasma membranes and thermal lability of [3H]dihydroalprenolol binding sites. Biochem Pharmacol 35:4387-93
Kawai, Y; Whitsel, C; Arinze, I J (1986) NADP+ enhances cholera and pertussis toxin-catalyzed ADP-ribosylation of membrane proteins. J Cyclic Nucleotide Protein Phosphor Res 11:265-74
Kawai, Y; Graham, S M; Whitsel, C et al. (1985) Hepatic adenylate cyclase. Development-dependent coupling to the beta-adrenergic receptor in the neonate. J Biol Chem 260:10826-32