The expression of desensitization of myocardial beta-adrenoceptor signal transduction system

1994 Fiscal Year Final Research Report Summary

• Project/Area Number: 05670587
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: ASAHIKAWA MEDICAL COLLEGE
• Principal Investigator: HASEBE Naoyuki ASAHIKAWA MEDICAL COLLEGE,FIRST DEPARTMENT OF INTERNAL MEDICINE,INSTRUCTOR, 医学部, 助手 (30192272)
• Project Period (FY): 1993 – 1994
• Keywords: WESTERN BLOTTING / ADENYLYL CYCLASE / POLYCLONAL ANTIBODY / MONOCROTALINE / NORTHERN BLOTTING / ADENYLYL CYCLASE TYPE V,VI cDNA / RIGHT VENTRICULAR HYPERTROPHY / ADENYLYL CYCLASE CATALYTIC UNIT

Research Abstract

Biochemical alteration in the beta-adrenoceptor transduction system, which underlie the diminishing response of the myocardium to catecholamines in failing hearts or aging heart, remains to be clarified. Recently, following the cloning of the first mammalian adenylyl cyclase, six full-length mammalian adenylyl cyclase isoforms and two partial clonings of other adenylyl cyclase have been reported.
1) We produced five different polyclonal antibodies against the partial sequence of adenylyl cyclase V of VI.However, the average titer of these antibodies was about 10-3. In addition, western blots of adenylyl cyclase from myocardial membranes in monocrotaline (MCT)-induced right ventricular hypertrophy and failure showed multiple bands. Although we recognized a band of 110kDa by these polyclonal antibodies, we could not detect strict tissue specificity.
2) We studied the alterations in myocardial mRNA levels of type V and VI adenylyl cyclase and its activity in rat heart with MCT-induced right ventricular hypertrophy and failure. These data suggested that a decrease in the steady state mRNA levels of type V and VI adenylyl cyclase paralleled with the impaired activity of the adenylyl cyclase catalytic subunit itself in the failing ventricle. However, adenylyl cyclase catalytic activity in the state of early hpertrophied ventricle without failure may be modulated by other mechanisms rather than its gene expression.
3) We investigated the developmental regulation fo beta-adrenoceptor-adenylyl cyclase pathway in myocardial membranes form fetal, neonatal, adults and mature adult rats by measuring the adenylyl cyclase enzyme, and the contribution of the respective steady-state mRNA levels. The age-related changes in the activity of the myocardial beta-adrenoceptor transduction system are regulated by the density of beta-adrenergic receptors and by the activity of the catalyst adenylyl cyclase. In particular, a decrease in the content of the type VI isoform of adenylyl cyclase underlies the pattern of decreasing catalytic activity with age.