The Enigmatic Cytoplasmic Regions of KCNH Channels

Abstract

KCNH channels are expressed across a vast phylogenetic and evolutionary spectrum. In humans they function in a wide range of tissues and serve as biomarkers and targets for diseases such as cancer and cardiac arrhythmias. These channels share a general architecture with other voltage-gated ion channels but are distinguished by the presence of an N-terminal Per-Arnt-Sim (PAS) domain and a C-terminal domain with homology to cyclic nucleotide binding domains (referred to as the CNBh domain). Cytosolic regions outside these domains show little conservation between KCNH families but within a family are strongly conserved across species, likely reflecting variability that confers specificity to individual channel types. PAS and CNBh domains participate in channel gating, but at least twice in evolutionary history the PAS domain has been lost, and in one family it is omitted by alternate transcription to create a distinct channel subunit. In this focused review we present current knowledge of the structure and function of these cytosolic regions, discuss their evolution as modular domains, and provide our perspective on the important questions moving forward.

Molecular Insights into the Mechanism of Calmodulin Inhibition of the EAG1 Potassium Channel

“…These are tetrameric channels that contain large cytoplasmic regions which serve as interfaces for modulatory inputs such as phosphorylation, interaction with kinases, integrins and calmodulin (Cherubini et al, 2005; Morais-Cabral and Robertson, 2015; Schonherr et al, 2000; Sun et al, 2004; Wang et al, 2002; Warmke and Ganetzky, 1994). The cytoplasmic regions include a PAS domain on the N terminus and a domain with homology to cyclic nucleotide binding domains (CNB-homology domain, CNBhD) on the C terminus; it has been shown that the PAS domain and the CNB-homology domain interact with each other (Gustina and Trudeau, 2011; Haitin et al, 2013).…”

Unfolding of a Temperature-Sensitive Domain Controls Voltage-Gated Channel Activation

“…Voltage-gated ion channels (VGICs) are exquisitely sensitive to transmembrane potential changes by virtue of a voltage-sensor domain that is embedded in the membrane bilayer (Vargas et al, 2012; Yu et al, 2005). Beyond the intrinsic ability to detect transmembrane voltage changes, VGIC superfamily members possess diverse intracellular domains (Yu et al, 2005) that are employed to tune voltage-dependent responses of a particular channel as a consequence of stimuli from signaling molecules (Morais-Cabral and Robertson, 2015; Yang et al, 2015). Although such domains provide a means for chemical cues to influence VGICs, the sensitivity to physical stimuli, such as temperature, in some VGIC superfamily members (Schneider et al, 2014; Vriens et al, 2014), has raised the question about whether there are equivalently specialized domains that can serve as temperature sensors (Bagriantsev et al, 2012; Brauchi et al, 2006; Grandl et al, 2008) or whether thermal responses arise from elements distributed throughout the channel (Chowdhury et al, 2014; Clapham and Miller, 2011).…”

hERG 1b is critical for human cardiac repolarization

“…Subsequently, alternate transcripts of KCNH2 in mouse and human heart were shown to encode two subunits: 1a (the original isolate) and 1b (6,7). In the hERG 1b transcript, an alternate 5′ exon replaces 1a exons 1-5, resulting in a shorter, unique N terminus that lacks a Per-Arnt-Sim (PAS) domain (also known as the ether-à-go-go domain) (8,9). In heterologous systems, hERG 1b subunits avidly associate with hERG 1a but fail as homomers to traffic efficiently to the plasma membrane (10).…”