LQT4 Gene: The “Missing” Ankyrin

Candidate mechanisms for intracellular Ca²⁺handling in ventricular myocytes. The proposed mechanisms are as follows: (1) β-adrenergic receptor (β-AR) stimulation, via G_s-mediated activation of adenylate cyclase (AC) and protein kinase A (PKA), phosphorylates phospholamban (PLB) to relieve PLB’s inhibition of the Ca²⁺-ATPase pump (SERCA) and, thereby, to enhance Ca²⁺ uptake by the sarcoplasmic reticulum (SR). (2) Ca²⁺-induced Ca²⁺-release (CICR) through the ryanodine receptor (RyR) is mediated by L-(or T-) type Ca²⁺ channel activation. (3) CICR via activation of voltage-dependent I_Na and the dual roles of the Na⁺/Ca²⁺ exchanger (NCX). (4) Ankyrin-mediated (blue spheres) localization of ion transport proteins via spectrin binding. (5) Ca²⁺ release triggered by inositol -1,4,5-trisphosphate (IP₃) through IP₃ receptors (IP₃R). (6) Inward rectifying K⁺ current (I_K1) maintains resting membrane potential and is sensitive to changes in [Ca²⁺]_i homeostasis. (7) CICR triggered by Ca²⁺ entry through tetrodotoxin (TTX)-sensitive Ca²⁺ channel. (8) Ca²⁺ release mediated by “slip mode conductance”, in which PKA-dependent phosphorylation of TTX-sensitive I_Na have altered permeability for Ca²⁺. (9) Ca²⁺-insensitve (I_TO,Ca) and Ca²⁺-sensitive (I_Cl,Ca) transient outward potassium channels, the latter of which is carried by Cl⁻ rather than K⁺ ions. (10) Reduced Ca²⁺-handling proteins due to a deficiency of ankyrin (blue spheres).