Ca2+ Controls Functional Expression of the Cardiac K+ Transient Outward Current via the Calcineurin Pathway

Calcineurin Increases Cardiac Transient Outward K+ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits

“…4 (C and D) and Table 1 show that I to,f densities along with G slope and G max were decreased in PEtreated myocytes compared with control myocytes without PE. However, contrary to expectations based on studies concluding that Cn is responsible for I to,f reductions (17,18), CAIN overexpression in PE-treated myocytes further reduced I to,f densi-FIGURE 2. Quantitation of mRNA levels (A) and representative images and quantitation of protein levels (B) of Kv4.2, Kv4.3, and KChIP2 in NRVMs overexpressing GFP or Cn.…”

“…Similarly, Cn activation (19,38,39) and I to,f reductions (10,11,14,18) are commonly observed in various animal models of cardiac hypertrophy and heart disease as well as in heart disease patients (40,41). Collectively, these observations have led to the suggestion that Cn activation is responsible for the reductions in I to,f (17,18) as well as hypertrophy. However, rather unexpectedly (17,18), our results showed that, in cultured NRVMs chronically treated with ␣ 1 AR agonists, inhibition of Cn (using CAIN) caused further reductions in I to,f , despite blocking hypertrophy, whereas overexpression of constitutively active Cn induced large increases in I to,f density without inhibiting myocyte hypertrophy.…”

“…Collectively, these observations have led to the suggestion that Cn activation is responsible for the reductions in I to,f (17,18) as well as hypertrophy. However, rather unexpectedly (17,18), our results showed that, in cultured NRVMs chronically treated with ␣ 1 AR agonists, inhibition of Cn (using CAIN) caused further reductions in I to,f , despite blocking hypertrophy, whereas overexpression of constitutively active Cn induced large increases in I to,f density without inhibiting myocyte hypertrophy. These changes in I to,f were associated with changes in mRNA and protein expression of Kv4.2, but not Kv4.3 or KChIP2, a pattern identical to that observed in the absence of ␣ 1 AR stimulation.…”

“…1A). Rather than decreasing I to,f , as might be expected from previous studies (17,18), Cn caused a 2-fold increase in I to,f density, which was quantified as the difference in the peak current minus the sustained current (I sus ) at the end of the pulse divided by the cell capacitance. I to,f density recorded at ϩ60 mV (Fig.…”

Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice

“…However, the dominant repolarizing current in cardiac ventricular myocytes is the transient outward current (I to ) (20). Recent studies (8,23,(35)(36)(37) have suggested that some of the cardiac K ϩ channel subunits that generate I to are tightly regulated by cytosolic Ca 2ϩ in their expression and activity, thus making regulation of the AP by I to in response to changes in Ca 2ϩ produced by knockout of NCX an attractive possibility.We report here that I to is increased in NCX KO mice and that the expression of the I to generating voltage-dependent K ϩ channel subunit Kv4.2 and the K ϩ channel interacting protein (KChIP) are upregulated. With the use of computer modeling, we further demonstrate that I to upregulation is the main determinant of AP shortening in KO mice.…”