Page 8 - CBAC Newsletter 2013

Two distinct Kir6.x subunits, Kir6.1 and Kir6.2, have been identified in K channels, with Kir6.1 having a single chan-
ATP
nel conductance that is approximately half that of Kir6.2. Furthermore, the Kir6.1 subunit is relatively less sensitive to
[ATP]i than Kir6.2 (Yamada, Isomoto et al. 1997). The SUR subunit is also heterogeneous with two isoforms - SUR1 and
SUR2. Additionally, two major SUR2 splice variants, SUR2a and SUR2b, add to the potential heterogeneity. In terms
of nucleotide sensitivity, SUR1 confers the highest sensitivity, SUR2B has intermediate sensitivity and SUR2A is the
least sensitive. Traditionally, pancreatic channels have been thought to be formed by Kir6.2 and SUR1 and cardiac
ventricular channels predominantly by Kir6.2 and SUR2a. Interestingly, the Kir6.1 (KCNJ8) and SUR2 (ABCC9) genes
are proximal on chromosome 12. Similarly KCNJ11 which encodes Kir6.2, and SUR1 (ABCC8) are also co-localized on
chromosome 11.

In some species, the available cardiac K ATP conductance has been shown to rival that of the excitatory Na current, I .
+
Na
However, in contrast to I , K is voltage-independent and when activated, will remain open throughout the duration
Na
ATP
of the action potential (AP). A delicate balance of currents during the AP plateau combined with persistently open and
highly conducting K will result in extreme shortening of AP duration (APD) with even a small fraction of channels open
ATP
(<1%) (Nichols, Ripoll et al. 1991, Shaw and Rudy 1997). This dramatic shortening with few channels open implies that
small changes in intracellular nucleotides may have significant effects on the whole cell electrophysiology.

The potential pro-arrhythmic consequences of K activation have been studied extensively by the Antzelevitch
ATP
group who has shown that myocytes with elevated conductance of the transient outward current (Ito) are particularly
susceptible to early termination by K (Di Diego and Antzelevitch 1993). Early termination is a consequence of several
ATP
factors. First, there is a strong pull toward negative potentials by repolarizing, outward Ito and K . In addition, there
ATP
is reduced depolarizing current from voltage-inactivated I as well as L-type Ca channels that have been inactivated
2+
Na
by intracellular Ca release. In combination, the reduced inward currents and increased outward current prevents
2+
recovery of I Ca,L from Ca -dependent inactivation and deactivates it, preventing the AP from proceeding to form a
2+
dome – hence the term “loss-of-dome” morphology. The proclivity of a localized group of myocytes to terminate early
can be extremely pro-arrhythmic, enabling neighboring regions with nominal APD to excite this region that has already
returned to its resting state.

Recent Experimental Findings

The ability of K activation to predispose patients to arrhythmias has recently garnered significant attention due to
ATP
the discovery of a link between ERS and mutations in Kir6.1. Patients carrying these mutations have electrocardio-
gram recordings with characteristic “J-waves”, which are thought to be mediated by I , consistent with early experi-
to
mental results demonstrating a mechanism for K induced arrhythmias discussed above. Functional examination of
ATP
KCNJ8-S422L via excised inside out patch showed that ATP sensitivity in mutant channels is dramatically reduced,
implying that mutant channels will open and remain open even at nominal intracellular ATP levels (Barajas-Martinez,
Hu et al. 2012). Still, the existence of a mutation in Kir6.1 that can cause arrhythmia goes against the prevailing theory
that Kir6.2 and SUR2a are the predominant ventricular K constituents.
ATP

Pharmacological approaches have recently been used to provide insight into the molecular composition of functional
K ATP channels. Using this strategy, in conjunction with genetically engineered mice, Flagg et al. probed the heteroge-
neous distribution of K in mouse heart and found that atrial myocyte K is primarily formed by Kir6.2 and SUR1,
ATP
ATP
while ventricular K channels were identified as Kir6.2 and SUR2a (Flagg, Kurata et al. 2008). However, K ATP channel
ATP
composition may vary depending on species, with the distribution in human myocytes being of primary interest (Fe-
dorov, Glukhov et al. 2011). To probe K in canine myocytes, which are more similar to human, we recently applied
ATP
the pharmacological approach of Flagg et al. In striking contrast to mouse, SUR2a was found to be the predominant
modulatory subunit in both atrial and ventricular canine myocytes (Zhang, Silva et al. 2012).

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