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S-Nitrosylation Induces Both Autonomous Activation and Inhibition of Calcium/Calmodulin-dependent Protein Kinase II δ

Jeffrey R Erickson1, C Blake Nichols2, Hitoshi Uchinoumi2

  • 1From the Department of Physiology, University of Otago, Dunedin 9016, New Zealand and.

The Journal of Biological Chemistry
|August 29, 2015
PubMed

Insights

Nitric oxide (NO) has a dual role in cardiac calcium/calmodulin (Ca(2+)/CaM)-dependent protein kinase II (CaMKII) regulation. NO can activate CaMKIIδ, but also inhibit its activation by Ca(2+)/CaM, impacting cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Biochemistry

Background:

  • Nitric oxide (NO) modulates cardiac cellular signaling, but its specific targets remain unclear.
  • Emerging evidence suggests NO activates calcium/calmodulin (Ca(2+)/CaM)-dependent protein kinase II (CaMKII) in the heart.
  • Understanding NO's role in cardiac CaMKII regulation is crucial for cardiovascular health.

Purpose of the Study:

  • To investigate the dual role of NO in regulating cardiac CaMKIIδ activity and its downstream effects.
  • To identify specific cysteine residues involved in NO-mediated modulation of CaMKIIδ.
  • To assess the impact of NO on CaMKIIδ activation and binding to CaM.

Main Methods:

  • Utilized a novel CaMKII activation sensor, Camui, to monitor cardiac CaMKIIδ activity.
  • Employed the NO donor S-nitrosoglutathione (GSNO) to study NO's effects on CaMKIIδ.
  • Introduced mutations at Cys-290 and Cys-273 to identify key regulatory sites.
  • Examined CaMKIIδ-dependent ryanodine receptor activation in adult cardiac myocytes.

Main Results:

  • NO exposure after Ca(2+)/CaM binding induced autonomous CaMKIIδ activation, dependent on Cys-290.
  • NO exposure prior to Ca(2+)/CaM binding inhibited CaMKIIδ activation and Ca(2+)/CaM interaction, dependent on Cys-273.
  • GSNO treatment affected CaM/CaMKIIδ binding and CaMKIIδ-dependent ryanodine receptor activation.

Conclusions:

  • NO exerts a dual regulatory effect on cardiac CaMKIIδ activity.
  • Cys-290 is critical for NO-induced activation, while Cys-273 mediates NO-induced inhibition.
  • These findings elucidate novel mechanisms of NO signaling in the heart, impacting calcium handling and cellular function.
Keywords:
Ca2+/calmodulin-dependent protein kinase II (CaMKII)S-nitrosylationnitric oxidenitrosylationprotein kinase

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