Ankyrins and human disease: what the electrophysiologist should know.

The coordinate activity of ion channels and transporters in cardiac muscle is critical for normal excitation-contraction coupling and cardiac rhythm. In the past decade, human gene variants, which alter ion channel biophysical properties, have been linked with fatal cardiac arrhythmias. Ankyrins are a family of "adaptor" proteins, which play critical roles in the proper expression and membrane localization of ion channels and transporters in excitable and nonexcitable cells. Recent findings demonstrate a new paradigm for human cardiac arrhythmia based not on gene mutations that affect channel biophysical properties, but instead on mutations that affect ion channel/transporter localization at excitable membranes in heart. Human ANK2 mutations are associated with "ankyrin-B syndrome" (an atypical arrhythmia syndrome with risk of sudden cardiac death). Human gene mutations, which affect ankyrin-G-based pathways for voltage-gated Na(v) channel localization, are associated with Brugada syndrome, a second potentially fatal arrhythmia. Together, these data demonstrate the importance of the molecular events involved in the cellular organization of membrane domains in excitable cells. Moreover, these data define an exciting new field of cardiac "channelopathies" due to defects in proper channel targeting/localization.