Myriad roles of voltage-activated potassium channel subunit Kvβ1.1 in the heart.

ELECTRICAL ABNORMALITIES within the heart can often result in the development of arrhythmias that may further progress into sudden cardiac death; often the origins of these developments remain largely unknown. Atrial fibrillation, which is one of the most common type of heart arrhythmia, affects an estimated 3–6 million people within the United States (Center for Disease Control). Arrhythmic events can arise in atria and or the ventricular regions of the heart, often developing from genetic mutations, in particular, from genes encoding important ion channels such as sodium and/or potassium channels and their auxiliary subunits. Research in the field of arrhythmic study identified key ion channels such as sodium and potassium channels, highlighting the clinical importance of mutations such as in the SCN5A channel (33). However, to date, potassium channel mutations as well as their auxiliary subunits alterations are less known and therefore remain important and clinically relevant targets for investigation. One particular group of potassium channels of interest are the voltage-activated potassium (Kv) channels, which play a critical role in establishing the repolarization phase of cardiac action potentials. In addition, they are one of the key channels affected in action potential prolongation as well as in QT prolongation. The human genome encodes roughly 40 different Kv channels, which are further subdivided into twelve subfamilies (Kv1– Kv12). They share a general channel mechanism, i.e., sensing voltage changes within the cell and responding by activating/ inactivating or closing, dependent upon the channel properties. Kv channels open, inactivate, and close in response to voltages, and this synchrony of Kv channel action works in continuous balance to propagate action potentials. Previous research identified that mutations of fast-inactivating Kv currents (murineKv4.2 human-Kv4.3 channels) demonstrated significant prolongation in QT durations, resulting in cardiac hypertrophy and even heart failure (4, 23). Mutations in other cardiac relevant Kv channels such as Kv2.1, 1.5, and 1.4 produced similar deleterious effects, altering QT durations with little to no effect demonstrated on cardiac remodeling (16, 17). Kv channel auxiliary subunit modulation has had profound effects on regulating Kv channel activity, which is sometimes even greater than mutations or deletions of the potassium channel (11, 19, 32). The auxiliary subunits or otherwise known -subunits Kv (Shaker potassium channel subunit) include Kv 1 (with splice variants Kv 1.1, Kv 1.2, and Kv 1.3) and Kv 2. These Kv subunits are of particular interest in the cardiovascular system because they are highly expressed within the heart and vascular system including the aorta (7, 25). In vitro work has demonstrated profound effects of Kv subunits on Kv channel activity, although little is known about the in vivo effects of Kv subunit alterations. Kv 1 subunits have been shown to modulate key Kv channels including Kv1.5, 1.4 and most recently 4.2 all of which play a vital role in the repolarization of cardiac action potentials (8, 25, 31). Kv 1 knockout mice have significant decrease in Ito,f as well as the Ito,s (1). More recent genetic testing is beginning to reveal the absence of Kv s in numerous disease conditions including schizophrenia, high blood pressure, and sudden cardiac death (3, 5, 12, 14). Initial discoveries demonstrated high levels of Kv subunits in brain and abundant expression in the heart as well as the vascular system (7). The cloning, isolation, purification, and X-ray crystallography work led to the understanding of the sequence and structure of the Kv subunits (9). The sequence alignment analysis showed that Kv subunits shared similarities with the oxidoreductases, in particular, the aldo-keto reductases (AKR) (15). Because of the closely related sequence to AKR5 and AKR7 subfamilies, the Kv subunits were later classified as AKR6 (10). Furthermore, the Kv subunits were recognized as the only protein with dual functions, both as an enzyme as well as modulator of Kv channels. These distinct characteristics categorized Kv subunits to an elite group of proteins known to us in nature. In addition, the unique ability of Kv subunits as reductase enzyme that convert carbonyls (aldehydes or ketones) to their respective alcohols shared the central feature of AKR’s proteins, i.e., the ability to bind pyridine nucleotides (NAD/NADH and NADP/NADPH) with high affinity. In this context, the findings by Tur and colleagues (29), reported in the current issue of the American Journal of Physiology-Heart and Circulatory Physiology, that Kv 1.1 interacts with NADH/NAD and alters cardiac electrical activity are highly novel. Subsequent research focused on understanding the Kv structure culminating in the crystal structure of a truncated Kv 2 subunit that remained bound to the NADP molecule during the crystallization process (9). In addition to the pyridine nucleotide binding abilities, the Kv 1 subunits with their varying NH2-termini demonstrated the potential to rapidly inactivate noninactivating Kv channels (2, 30). Moreover, even fast-inactivating Kv channels such as Kv1.4 as well as Kv4.2/4.3 could be modulated by Kv 1 subunits (6, 20, 22). Much like the other oxidoreducastases, the Kv subunits maintained substrate binding sites and cofactor binding pockets. While it was understood that pyridine nucleotides could Address for reprint requests and other correspondence: R. C. Kukreja, Scientific Director, Pauley Heart Ctr., Div. of Cardiology, Box 980204, Virginia Commonwealth Univ., 1101 E. Marshall St., Rm. 7-020D, Richmond, VA 23298-0204 (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 312: H546–H548, 2017; doi:10.1152/ajpheart.00005.2017.