Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels

Abstract

Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long-QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long-QT syndrome by direct block of the rapid delayed rectifier (IKr) also seem to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes mellitus also may result from changes in multiple currents because of decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the effect of PI3K and its downstream effectors, including Akt, on sodium, potassium, and calcium currents in cardiac myocytes. We also refer to some studies in noncardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility.

Keywords: Cav1.2 calcium channel; Kv11.1 voltage-gated channel; Kv7.1 potassium channel; Nav1.5 voltage-gated sodium channel; human; long QT syndrome.

Figure 1. PI3K signaling pathways regulating cardiac ion channels

Receptor tyrosine kinases (RTKs) such as the insulin receptor activate PI3Kα to produce PI(3,4,5)P₃, which recruits Akt and PDK1 to the plasma membrane, resulting in Akt activation. RTKs can also activate atypical PKCs (aPKC) and SGK via PDK1. Gβγ subunits released from G protein-coupled receptors (GPCRs) activate PI3Kγ to increase PI(3,4,5)P₃ production and activate Akt, but the Gα_q subunits inhibit PI3Kα. Akt, PDK1, aPKC, SGK and possibly other downstream effectors of PI3K regulate ion channels that conduct potassium, sodium and calcium currents. PTEN dephosphorylates PI(3,4,5)P₃ to antagonize PI3K signaling. PI3Kγ also binds to and activates phosphodiesterases (PDE) to decrease cAMP, a second messenger that regulates many cardiac ion channels. This function of PI3Kγ is independent of its kinase activity.

Figure 2. Hypothetical modes of regulation of cardiac sodium currents by PI3Kα

Phosphorylation of Na_v1.5 by PI3Kα/Akt suppresses the persistent sodium current; this effect is reversed by inhibitors of PI3K/Akt signaling and diabetes. Phosphorylation of Na_v1.5 by SGK1 on a separate site might increase the persistent current. Phosphorylation of NEDD4-2 by kinases downstream of PI3Kα increases peak sodium current by maintaining Na_v1.5 on the cell surface. In the presence of PI3K inhibitors, NEDD4-2 is dephosphorylated, it binds to and ubiquitinates Na_v1.5, and the channel is internalized. PI3Kα upregulates transcription of the sodium channel gene SCN5A by Akt-dependent phosphorylation and inactivation of the transcription repressor FOXO1 and by an unknown Akt-independent mechanism.

Figure 3. Hypothetical regulation of cardiac delayed rectifier currents by PI3Kα

Phosphorylation of NEDD4-2 by kinases downstream of PI3Kα increases the currents by preventing the ubiquitination and internalization of the two channels. In the presence of PI3K inhibitors or diabetes, NEDD4-2 is dephosphorylated, it binds to and ubiquitinates K_v7.1 and K_v11.1, and the channels are internalized. PI3Kα may also increase cell surface expression of the channels by a second mechanism that involves phosphorylation of PIKfyve and activation of Rab11-mediated trafficking of channel subunits located in intracellular vesicles (circle) to the cell surface. PI3Kα also upregulates transcription of the potassium channel genes KCNH2 and KCNQ1 by unknown mechanisms.

Figure 4. Hypothetical regulation of the cardiac L-type calcium current by PI3Ks

PI3Kα/Akt increases the current by upregulating the cell surface localization and increasing the stability of Ca_v1.2 as a result of Ca_vβ2 phosphorylation. The current is decreased in the presence of PI3K inhibitors, Gα_q and in diabetes due to channel internalization. PI3Kα activation of effectors including atypical PKC (aPKC) also affects gating, perhaps through phosphorylation of Ca_v1.2. PI3Kα also upregulates transcription of the gene that encodes Ca_v1.2 (CACNA1C) by an unknown mechanism. PI3Kγ activation of a phosphodiesterase (PDE) decreases cAMP to affect the current.