Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets

Area of Science:

• Cardiology
• Molecular Biology
• Cellular Physiology

Background:

• Calcium-calmodulin dependent protein kinase IIδ (CaMKIIδ) regulates critical cardiac functions including electrophysiology, calcium handling, contraction, and heart failure progression.
• CaMKIIδ activation typically occurs near dyadic cleft calcium channels, but its mobility and activation at extra-dyadic sites remain unclear.

Purpose of the Study:

• To investigate the mobility of CaMKIIδ in adult rabbit cardiomyocytes.
• To determine how kinase activation influences CaMKIIδ mobility and its distribution within the cell.

Main Methods:

• Utilized immunocytochemistry and fluorescence microscopy techniques, including fluorescence recovery after photobleach (FRAP) and photoactivation of fluorescence.
• Measured the translocation of both endogenous and fluorescence-tagged CaMKIIδ in cardiomyocytes under resting and stimulated conditions.

Main Results:

• Contrary to the prevailing view, CaMKIIδ demonstrated high mobility in resting cardiomyocytes.
• CaMKIIδ mobility was reduced by calcium chelation and significantly increased by pacing.
• CaMKIIδ translocated from Z-lines near dyads to the broader sarcomere upon pacing, with enhanced nuclear exchange during chronic activation (pacing and heart failure).

Conclusions:

• CaMKIIδ is highly mobile in cardiomyocytes, challenging the notion of it being rigidly anchored.
• Pacing-induced mobilization of active CaMKIIδ, coupled with its intrinsic memory, facilitates broader target engagement, potentially influencing cardiac function and disease progression.