It had been known since 1969 that potassium currents with unique kinetic and voltage-dependent properties were important to the cardiac action potential plateau (31
). Because of the unique voltage dependence, these currents were referred to as delayed rectifiers. In a pivotal study, Sanguinetti and Jurkiewicz used a pharmacologic analysis to demonstrate 2 distinct components of the delayed rectifier potassium current in the heart: IKr
). The IKs
component had previously been shown to be under control of the sympathetic nervous system, providing an increase in repolarization currents in the face of β-AR agonists in cellular models (34
), but the molecular identity and the relevance to human electrophysiology were not only unclear, but controversial. The clear clinical importance and the genetic basis of these potassium currents were revealed through LQTS investigations.
The first report linking potassium channel dysfunction to LQTS revealed the molecular identity of 1 of the delayed rectifier channels and confirmed the pharmacologic evidence for independent channels underlying these currents (35
). This ground-breaking study, a collaborative effort between clinical and basic scientists, revealed that KCNH2 encodes the α (pore-forming) subunit of the IKr
channel and that the rectifying properties of this channel, identified previously by pharmacologic dissection, are indigenous to the channel protein. This work not only provided the first clear evidence for a role of this channel in the congenital LQTS but also laid the base line for future studies that would show that it is the KCNH2 channel that underlies almost all cases of acquired LQTS (36
The next breakthrough came in 1996 when a collaborative clinical/basic effort discovered that LQTS variant 1 (LQT1) was caused by mutations in a gene (KCNQ1) coding for an unusual potassium channel subunit that could be studied in heterologous expression systems (37
). Basic studies almost immediately revealed the functional role of the KCNQ1 gene product: the α (pore-forming) subunit of the IKs
). Furthermore, these studies indicated that a previously reported but as-yet poorly understood gene (KCNE1) formed a key regulatory subunit of this important channel. Mutations in KCNE1 have subsequently been linked to LQT5 (40
). Now the molecular identity of the 2 cardiac delayed rectifiers had been established.
As is summarized above, clinical studies had provided convincing evidence linking sympathetic nerve activity and arrhythmia susceptibility in LQTS patients, particularly in patients harboring LQT1 mutations. These data and previous basic reports of the robust sensitivity of the slow delayed rectifier component, IKs
, to β-AR agonists (34
) motivated investigation of the molecular links between KCNE1 channels and β-AR stimulation, which revealed, for the first time, that the KCNQ1/KCNE1 channel is part of a macromolecular signaling complex in the human heart (41
). The channel complexes with an adaptor protein called Yotiao that in turn directly binds key enzymes in the β-AR signaling cascade (protein kinase A and protein phosphatase 1) and recruits them to form a local signaling environment to control the phosphorylation state of the channel. Mutations in either KCNQ1 (41
) or KCNE1 (42
) can disrupt this regulation and create heterogeneity in the cellular response to β-AR stimulation, a novel mechanism that may contribute to the triggering of some arrhythmias in LQT1 and LQT5 (43
). This fundamental work is a direct consequence of collaborative efforts between basic and clinical investigators.