Fitting KV potassium channels into the PIP2 puzzle: Hille group connects dots between illustrious HH groups

In the August 2012 issue of the JGP, the Bertil Hille group continues its exploration of the physiological significance and cell signaling roles of PIP2 interactions with potassium channels. As we have come to expect, the group brings surprises and deep insights. In their article (Kruse et al., 2012), they have tackled the question of which voltage-gated potassium (KV) channels may be affected by, and therefore regulated by, changes of PIP2 that can occur in intact cells. The work brings equally clarity and sobriety to an area of ion channel regulation that has seen false starts. Whereas most, if not all, inward rectifier potassium channels are strongly PIP2 dependent, the situation with KV channels is very different. PIP2 effects on KV channels can be large, small, variable, or absent, and PIP2 can evidently modify primarily activation/deactivation parameters, inactivation, or channel availability per se in different cases. Two cases can illustrate the nature of the issues at hand for KV channels. First, many KV channels, like other channels, are functionally labile in excised patches. Knowing that PIP2 activates many ion channels, we tested many years ago whether the notoriously labile KV2.1 channels (Zühlke et al., 1994) might be stabilized in excised patches by incorporating PIP2. In our hands, the KV2.1 channels were completely rescued from rundown and remained stable for unlimited recording periods (Hilgemann et al., 2001). Second, as just noted, KV channel inactivation can be drastically “PIP2 dependent” in excised patches. When recording KV1.1 or KV3.4 channel currents in excised patches, the application of PIP2 micelles to the cytoplasmic side of patches can rapidly abolish inactivation (Oliver et al., 2004). One explanation for the inactivation block is that PIP2 interacts with the positively charged inactivation domain of KV channels. Similar to suggestions for Na/Ca exchangers (Hilgemann and Ball, 1996; He et al., 2000), positively charged inactivation domains might be able to reach and bind to PIP2 in the plasmalemma, thereby preventing them from causing inactivation. Both of these cases, and others, suggested to many of us that PIP2 would turn out to be a very important regulator of KV channels.