The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology

Abstract

The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and functionally regulating the voltage-gated potassium channels, the broad influence of KCNE subunits in mammalian physiology belies their small size. KCNE2 has been widely studied since we first discovered one of its roles in the heart and its association with inherited and acquired human Long QT syndrome. Since then, physiological analyses together with human and mouse genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. The other side of this coin is the variety of interconnected disease manifestations caused by KCNE2 disruption, involving both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia. Kcne2 deletion in mice has been particularly instrumental in illustrating the potential ramifications within a monogenic arrhythmia syndrome, with removal of one piece revealing the unexpected complexity of the puzzle. Here, we review current knowledge of the function and pathobiology of KCNE2.

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

“…Interestingly, this was the first interaction reported between a channel and a transporter, and it was followed by the discovery of another physiologically relevant interaction between KCNQ1 and KCNE2 and the Na + -coupled myoinositol transporter, a member of the same family as NIS found in the choroid plexus of mice (47). These studies make it clear that channels and transporters do not necessarily function in isolation but, instead, they often regulate each other (48). …”

KCNE1 and KCNE3: The yin and yang of voltage-gated K+ channel regulation

“…Although the five KCNE genes share relatively little similarity with one another, they each exhibit 1-TM topology with an extracellular N-terminal domain and intracellular C-terminal domain. In addition, each possesses a consensus protein kinase C (PKC) phosphorylation site in the membrane-proximal portion of the cytoplasmic C-terminal region 19 . BLAST searching with features of KCNE1 known to be important for its function circumvented the difficulties presented by relatively low family-wide sequence identity, and uncovered KCNE2, 3 and 4 – which we initially termed MinK-related peptides (MiRPs) 1, 2 and 3 16 .…”

“…This review covers the mechanisms and physiological roles of KCNE1 and KCNE3 regulation of KCNQ1 and other Kv channels. A recent companion review was focused on KCNE2 19 .…”

Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4

“…Fits were made to mean data and therefore P values are not available for comparisons between groups, but Chi2 values are given to indicate goodness of fit. For graphs of fits see Fig.…”

“…In addition, native Kv channels are large macromolecular complexes composed of multiple different pore-forming α subunits, regulatory (β) subunits, and other even more promiscuous regulatory proteins not limited to ion channel regulation. The various regulatory subunits further enhance the native Kv current repertoire, facilitate specialization for specific α subunits to conduct diverse functions in different cell types, and help to shape currents during different stages of development, or diversify Kv currents between sexes and different life stages by responding to hormones123.…”