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G protein coupled receptor kinase-2 upregulation causes κ-opioid receptor desensitization in diabetic heart

Xiyao Chen1, Shihao Zhao2, Yunlong Xia2

  • 1Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.

Biochemical and Biophysical Research Communications
|November 21, 2016
PubMed

Insights

High glucose impairs heart protection from κ-opioid receptor (KOR) activation in diabetes. Upregulated GRK2 causes KOR desensitization, offering new therapeutic targets for myocardial ischemia/reperfusion injury.

Area of Science:

  • Cardiovascular Biology
  • Endocrinology
  • Molecular Medicine

Background:

  • κ-opioid receptor (KOR) activation protects against myocardial ischemia/reperfusion (I/R) injury.
  • This cardioprotective effect is lost in diabetic individuals with hyperglycemia.
  • The underlying molecular mechanisms remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms of KOR desensitization in the diabetic heart.
  • To identify the role of G protein coupled receptor kinase-2 (GRK2) in high glucose-induced KOR downregulation.

Main Methods:

  • Studied streptozotocin (STZ)-induced diabetic mice and cultured cardiomyocytes.
  • Utilized high glucose (HG) exposure, GRK2 inhibition via siRNA, and cardiac-specific GRK2 knockdown.
  • Assessed KOR expression, GRK2 interaction with KOR, and protection against simulated I/R injury.

Main Results:

  • Diabetic mouse hearts showed downregulated KOR and impaired KOR agonism effects.
  • High glucose downregulated KOR and upregulated GRK2 in cardiomyocytes, increasing GRK2-KOR interaction.
  • GRK2 inhibition/knockdown reversed HG-induced KOR downregulation and restored cardioprotection.

Conclusions:

  • Cardiac KOR desensitization is a characteristic of the diabetic heart.
  • GRK2 upregulation is a key mediator of high glucose-induced KOR desensitization.
  • Targeting GRK2 may restore KOR-mediated cardioprotection in diabetic patients.
Keywords:
DiabetesG protein coupled receptor kinase-2Ischemia/reperfusionκ-opioid receptor

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