Discovery of a heme-binding domain in a neuronal voltage-gated potassium channel

Abstract

The ether-à-go-go (EAG) family of voltage gated K+ channels are important regulators of neuronal and cardiac action potential firing (excitability) and have major roles in human diseases such as epilepsy, schizophrenia, cancer and sudden cardiac death. A defining feature of EAG (Kv10-12) channels is a highly conserved domain on the amino-terminus, known as the eag-domain, consisting of a PAS domain capped by a short sequence containing an amphipathic helix (Cap-domain). The PAS and Cap domains are both vital for the normal function of EAG channels. Using heme-affinity pull-down assays and proteomics of lysates from primary cortical neurons, we identified that an EAG channel, hERG3 (Kv11.3), binds to heme. In whole cell electrophysiology experiments, we identified that heme inhibits hERG3 channel activity. In addition, we expressed the Cap and PAS domain of hERG3 in E.coli and, using spectroscopy and kinetics, identified the PAS domain as the location for heme binding. The results identify heme as a regulator of hERG3 channel activity. These observations are discussed in the context of the emerging role for heme as a regulator of ion channel activity in cells.

Understanding the Logistics for the Distribution of Heme in Cells

“…This could be used as a versatile mechanism for cell signaling. Examples of heme-dependent regulation are beyond the scope of this review but have been summarized recently. , They include, among others, transcriptional regulation and gas sensing, ,, degradation of the p53 protein, regulation of the circadian clock, − immune response, , aging, and the gating of numerous ion channels. − …”

Cyclic nucleotide‐dependent ionic currents in olfactory receptor neurons of the hawkmoth Manduca sexta suggest pull–push sensitivity modulation

“…We hypothesize that I K(cGMP+) is based on channels from the ether‐á‐go‐go (EAG) channel family found in Manduca antennae (Bauer & Schwarz, 2001; Keyser et al, 2003; Stansfeld et al, 1996; Wicher et al, 2001). They are structurally related to Shaker , but also to the CNG channels (Brüggemann et al, 1993; Burton et al, 2020; Chen et al, 2000). Furthermore, I K(cGMP+) expressed slow inactivation when the membrane potential was stepped from negative holding potential to more positive values, characteristic for currents generated by EAG‐type channels (Keyser et al, 2003; Ludwig et al, 1994; Robertson et al, 1996).…”

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

“…In addition, KCa channels have emerged as a potential therapeutic tool for aging and age-related neurodegeneration [ 49 ]. Kv channels involve a variety of physiological processes ranging from triggering neuronal and cardiac action potential to regulating cell cycle and cell volume, to driving cellular proliferation and migration [ 16 , 50 ]. These Kv channels have a major role in human diseases such as cancer, schizophrenia, epilepsy, and sudden cardiac death [ 50 , 51 , 53 ].…”

“…Kv channels involve a variety of physiological processes ranging from triggering neuronal and cardiac action potential to regulating cell cycle and cell volume, to driving cellular proliferation and migration [ 16 , 50 ]. These Kv channels have a major role in human diseases such as cancer, schizophrenia, epilepsy, and sudden cardiac death [ 50 , 51 , 53 ]. In recent years, emerging evidence demonstrates that the Kv channel is becoming an oncological target since targeting it can reduce tumor growth and progression in vitro and in vivo [ 52 , 121 , 122 , 123 ].…”