AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K+ currents in ventricular myocytes following myocardial infarction

Abstract

The Ca2+-responsive phosphatase calcineurin/ protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K+ (Kv) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca2+ signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of Kv channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150-calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of Kv channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of Kv currents.

Calcineurin signaling in the heart: The importance of time and place

“…Thus, input from LTCC localized to caveolae plays an important role in specifying LTCC/calcineurin/NFATc3 signaling. This is supported by studies demonstrating that cardiomyocytes isolated from mice lacking AKAP5 or expressing a mutant form of AKAP5 deleted for the calcineurin PxIxIT binding motif (AKAP5-ΔPIX) are unable to sustain nuclear translocation of NFATc3 in response to adrenergic stimulation [155]. …”

“…The α MHC-CnA * transgenic mice have a significant reduction in I to density that can be reversed by treatment with CsA [172]. In isolated adult cardiomyocytes and intact hearts calcineurin decreases I to , in part through AKAP5-dependent activation of NFATc3 leading to transcriptional repression of the expression of several K + channel subunits including Kv4.3, Kv4.2, and KChIP2 [155, 173, 174]. The mechanism of NFATc3-dependent repression is not fully understood and could be secondary to expression of an unidentified repressor.…”

Potassium channels in the heart: structure, function and regulation

“…Conversely, the anchoring protein AKAP79/150 is required for calcineurin/NFATc3‐mediated transcriptional downregulation and functional suppression of K V channels following myocardial infarction (Nieves‐Cintron et al . ). These observations underscore the extensive functional diversity that may coexist within a cell to contribute to a specific phenotype.…”

Cardiac function modulation depends on the A‐kinase anchoring protein complex

“…AKAP79/150 interacts with PKA, protein kinase C(PKC), Ca 2+ /calmodulin‐dependent phosphatase (CaN), calmodulin (CaM) and other signalling molecules to regulate vascular tone and blood pressure …”

“…AKAP79/150 interacts with PKA, protein kinase C(PKC), Ca 2+ / calmodulin-dependent phosphatase (CaN), calmodulin (CaM) and other signalling molecules to regulate vascular tone and blood pressure. [28][29][30]69,70 During hyperglycaemia and diabetes, AKAP79/150 is reported to contribute to enhancing vascular tone through facilitating largeconductance Ca 2+ -activated K + (BK) channel remodelling. AKAP150…”