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Published on: April 16, 2018
Opioid Peptide gene expression in the myocardial cell
C Ventura1, G Pintus, B Tadolini
1Department of Biomedical Sciences, Division of Biochemistry, Laboratory of Cardiovascular Research, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy; National Laboratory of the National Institute of Biostructures and Biosystems, Osilo, Italy.
Abstract:
Both κ and δ opioid receptors have been identified in the myocardial cell. These receptors are coupled to phosphoinositide turnover and protein kinase C (PKC) activation, and their stimulation affects the cytosolic Ca(2+) and pH homeostasis as well as the contractility and the myofilament responsiveness to Ca(2+). Both the proenkephalin and the prodynorphin gene are expressed in cardiac myocytes. These cells are also able to synthetize and secrete dynorphin B, a biologically active end product of the prodynorphin gene binding selectively the κ opioid receptor. Prodynorphin mRNA and dynorphin B expression are markedly increased in ventricular myocytes isolated from Syrian cardiomyopathic hamsters (the hypertrophic BIO 14.6 strain), as compared with normal cells. Nuclear PKC activation and intracellular Ca(2+) overload have been shown to act as the two major signaling mechanisms involved in the increase in prodynorphin gene transcription observed in cardiomyopathic myocytes. In these cells, secreted dynorphin B activates κ opioid receptors at the cell surface and elicits an autocrine loop, leading to an increase in nuclear PKC activity and to a tonic feed-forward stimulation of prodynorphin gene transcription. The possibility that opioid genes may act in an autocrine fashion to affect myocardial Ca(2+) homeostasis, growth, and differentiation is also discussed.
Insights
Cardiac myocytes express opioid receptors that regulate calcium and contractility. In cardiomyopathic hamsters, dynorphin B overproduction creates an autocrine loop, increasing prodynorphin gene transcription.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Neuropharmacology
Background:
- Myocardial cells express kappa (κ) and delta (δ) opioid receptors.
- Opioid receptor stimulation influences intracellular calcium (Ca2+), pH, and contractility.
- Cardiac myocytes express proenkephalin and prodynorphin genes.
Purpose of the Study:
- Investigate the role of opioid receptors and genes in cardiac function.
- Examine dynorphin B synthesis and secretion in cardiomyopathic hearts.
- Elucidate signaling pathways involved in prodynorphin gene regulation.
Main Methods:
- Isolation of ventricular myocytes from Syrian cardiomyopathic hamsters (BIO 14.6 strain) and normal controls.
- Measurement of prodynorphin mRNA and dynorphin B expression.
- Analysis of nuclear protein kinase C (PKC) activation and intracellular Ca2+ levels.
Main Results:
- Prodynorphin mRNA and dynorphin B levels are significantly elevated in cardiomyopathic myocytes.
- Nuclear PKC activation and Ca2+ overload are key signaling mechanisms driving increased prodynorphin transcription.
- Secreted dynorphin B activates cell surface κ opioid receptors, creating an autocrine loop that enhances PKC activity and prodynorphin gene transcription.
Conclusions:
- Dynorphin B acts in an autocrine manner in cardiomyopathic hearts.
- This autocrine signaling loop contributes to altered myocardial Ca2+ homeostasis and potentially cardiac growth.
- Opioid gene expression may play a significant role in the pathophysiology of cardiac hypertrophy and dysfunction.
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