Ion channels as part of macromolecular multiprotein complexes

Figures

• 

  Fig. 1. The role of ion channel macromolecular complexes in cardiac electrophysiology and arrhythmogenesis. a Schematic representation of the cardiac action potential and the major underlying ion currents. I Na fast Na+ current, I to transient-outward K+ current, I Ca,L L-type Ca2+ current, I Kr rapid delayed-rectifier K+ current, I Ks slow delayed-rectifier K+ current, I NaK Na+-K+-ATPase current, INCX Na+/Ca2+ exchanger current; I K1 basal inward-rectifier K+ current. b Macromolecular complexes ensure proper trafficking, localization and function of ion channels, thereby preventing occurrence of ectopic activity and reentry, the primary mechanisms of cardiac arrhythmias. This regulation may be disturbed by genetic mutations or impaired expression of individual components of the macromolecular complex. ERP effective refractory period

• 

  Fig. 2. Regulation of ion channels and sarcoplasmic reticulum (SR) Ca2+-handling proteins through macromolecular complexes. a The composition of the macromolecular complex controls: 1 Trafficking, localization and mechanosensitive regulation of ion channels and Ca2+-handling proteins, e. g., through regulatory subunits (cyan ellipses) that mask endoplasmic reticulum retention signals or proteins interacting with various components of the cytoskeleton (red); 2 Posttranslational modifications, e. g., phosphorylation (orange “P”) through anchoring of protein kinases (PK), phosphatases (PP) and other enzymes (green); 3 Ca2+-dependent regulation, e. g., mediated by calmodulin (purple); and 4 Channel gating and biophysical properties, e. g., through regulatory subunits. b Example of the macromolecular complex controlling the slow delayed-rectifier K+ current (I Ks). The channel consists of a tetramer of Kv7.1 pore-forming α subunits, KCNE1 β subunits, an A‑kinase anchoring protein (Yotiao) that targets protein kinase A (PKA), protein phosphatase type-1 (PP1), adenylyl cyclase (AC), and phosphodiesterase (PDE) 4D3 to the channel, as well as the Ca2+-binding protein calmodulin (CaM), protein…