Heme impairs the ball-and-chain inactivation of potassium channels

Abstract

Significance Heme, traditionally viewed as a stable protein cofactor such as in hemoglobin, also serves as an acute signaling molecule and is cytotoxic at high concentrations. Here, we show that free intracellular heme potently enhances A-type potassium channel function. Such channels determine action potential frequency in excitable cells, and their dysfunction often contributes to pathological hyperexcitability, such as in pain and epilepsy. Binding of free heme at nanomolar concentrations to the “ball-and-chain” N terminus of A-type potassium channels, which typically closes the channels, introduces a stable structure in the otherwise disordered region and allows for a greater efflux of potassium ions, thus reducing cellular excitability. Heme therefore could be a powerful negative-feedback regulator in brain and muscle function.

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

“…The high affinity binding of heme to Slo1 decreases the frequency of channel opening leading to an inhibition of transmembrane K+ currents[44, 45]. Its binding to the N-terminal domain of Kv1.4 channels inhibits the fast inactivation of the channel, thus reducing cellular excitability[46]. …”

A heme-binding domain controls regulation of ATP-dependent potassium channels

“…In the case of ion channel regulation, it has recently emerged that there is a role for heme (12,(23)(24)(25)(26), but the observations are largely empirical, so that the molecular basis for the regulatory control within individual channel proteins has yet to be properly defined. A number of heme-responsive motifs (27) have been suggested to be involved: these include Cys/Pro (CP) motifs using thiolate ligation to the heme as in the P450s or Cys/His motifs (3,14).…”

“…Such flexibility of heme binding-particularly flexibility of Cys ligation and particularly redox-linked ligation changes (15)-seems to be a feature of these regulatory heme proteins; it probably reflects an intrinsic mobility of the protein structure (as evidenced by the conformational changes leading to low-spin heme formation) that can, potentially, absorb binding of heme in more than one orientation. A mixture of binding modes have been suggested for the Kv1.4 ball peptide-hemin complex (23).…”

Digested disorder, Quarterly intrinsic disorder digest (October-November-December, 2013)

“…Sahoo et al 43 showed that heme can physically bind to the ball domain and inhibit its ability to inactivate the K C channel by increasing structural order.…”