# Casein Kinase 2 Regulates the Intrinsic Activity of L-Type Calcium Currents in Cardiomyocytes

## TL;DR

This study shows that casein kinase 2 (CK2) regulates calcium currents in heart cells, which could impact heart failure.

## Contribution

The novel finding is that CK2 phosphorylates calmodulin to regulate L-type calcium currents in cardiomyocytes.

## Key findings

- Silencing CK2 or inhibiting it pharmacologically reduces L-type calcium currents by ≈75%.
- Phosphomimetic CaM variants counteract the downregulation of calcium currents caused by CK2 knockdown.
- CK2 and PKA work together to regulate calcium currents, with CK2 phosphorylation exacerbating calcium overload in heart failure.

## Abstract

Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational modification was investigated in cultured cardiomyocytes. Whole-cell LTCCs decreased by ≈75% after silencing the gene coding for casein kinase 2 (CK2), a constitutively active kinase in cardiomyocytes, or after its pharmacological inhibition. The overexpression of the dominant negative phosphoresistant single, double T79A/S81A, or triple T79A/S81A/S101A CaM variants resulted in a similar inhibition. In contrast, the overexpression of CaM WT or its double T79D/S81D and triple T79D/S81D/S101D phosphomimetic variants curtailed the downregulation of LTCCs caused by CK2 partial knockdown, suggesting that CK2 is responsible for the posttranslational modification of these CaM target residues. Catecholamines, triggering the protein kinase A (PKA) cascade, partially rescued LTCCs treated with siRNA without or after the overexpression of either CaM WT or stimulating CaM phosphomimetic variants. More importantly, they thwarted the negative impact of the phosphoresistant CaM variants, altogether arguing that CK2 and PKA are acting in synergy to regulate the activity of LTCCs. We conclude that CK2-mediated phosphorylation processes exacerbate the Ca2+ load associated with heart failure.