Background:

The large conductance voltage- and Ca²⁺-activated potassium (BK) channels (maxi-K⁺ channels) hyperpolarize the cell membrane and thus support Ca²⁺ entry through Ca²⁺ release activated Ca²⁺ channels. BK channels thus participate in the machinery regulating cell proliferation and migration. BK channels are expressed in a variety of tumor cells. Regulation of cell proliferation involves Janus-activated kinase-2 (JAK2). The gain of function mutation ^V617FJAK2 is found in the majority of myeloproliferative diseases. The present study thus explored whether JAK2 participates in the regulation of BK channels.

Methods:

Ca²⁺ insensitive BK channels (BK^{M513I+δ899-903}) were generated by site directed mutagenesis. cRNA encoding those channels was injected into Xenopus oocytes with or without wild type JAK2, ^V617FJAK2 or inactive ^K882EJAK2 and K⁺ conductance determined by dual electrode voltage clamp.

Results:

The K⁺ current in BK-expressing oocytes was significantly increased following coexpression of ^V617FJAK2, but was significantly decreased by coexpression of ^K882EJAK2. Exposure of BK and ^V617FJAK2 expressing oocytes to the JAK2 inhibitor AG490 (40 µM) resulted in a gradual decline of the K⁺ current. The decline of the K⁺ current following inhibition of channel insertion by brefeldin A (5 µM) was similar in oocytes coexpressing BK channels and ^V617FJAK2 as in oocytes expressing BK channels alone, indicating that ^V617FJAK2 stimulates channel insertion into rather than inhibiting channel retrieval from the cell membrane.

Conclusions:

JAK2 is a powerful stimulator of BK channels.