A-kinase anchoring protein 9 and IKs channel regulation

Abstract

A-kinase anchoring proteins (AKAPs) create compartmentalized environment inside the cell to bring various signaling molecules to their targets. In the heart, a slowly activating potassium channel (IKs) important for cardiac repolarization is tightly regulated by the sympathetic nervous system in an AKAP-dependent manner. IKs channel forms a macromolecular complex with AKAP9 and other enzymes, such as protein kinase A, phosphatase, adenylyl cyclase, and phosphodiesterase, all of which are responsible to control the phosphorylation state of the channel. Such a complex thus ensures the IKs channel to be regulated properly to maintain the normal cardiac rhythm. Disruptions of various elements of the complex have been found to cause severe pathological consequences, including the long QT syndrome.

Figure 1

A schematic diagram of the I_Ks /AKAP9 (Yotiao) macromolecular complex. I_Ks channels are comprised of α-subunits (KCNQ1) and β-subunits (KCNE1). S27 is a PKA phosphorylation site on KCNQ1 N-terminus. AKAP9 interacts with KCNQ1 C-terminus and harbors two pairs of enzymes that control the phosphorylation state of the channel. PKA phosphorylates I_Ks channel, while PP1 dephosphorylate it. AC and PDE control cAMP level, which in turn activates PKA.