Kv Channel Ancillary Subunits: Where Do We Go from Here?

Abstract

Voltage-gated potassium (Kv) channels each comprise four pore-forming α-subunits that orchestrate essential duties such as voltage sensing and K+ selectivity and conductance. In vivo, however, Kv channels also incorporate regulatory subunits—some Kv channel specific, others more general modifiers of protein folding, trafficking, and function. Understanding all the above is essential for a complete picture of the role of Kv channels in physiology and disease.

G protein βγ regulation of KCNQ-encoded voltage-dependent K channels

“…The biophysical, pharmacological and trafficking properties of Kv7 channels are also dictated by association with proteins encoded by the KCNE gene family (KCNE1-5, Abbott, 2020 ; 2022 ). The best studied of Kv7-KCNE interactions is Kv7.1 and KCNE1, which constitute channel responsible for the slowly activating late component of ventricular and atrial action potential repolarisation ( Barhanin et al, 1996 ).…”

“…The best studied of Kv7-KCNE interactions is Kv7.1 and KCNE1, which constitute channel responsible for the slowly activating late component of ventricular and atrial action potential repolarisation ( Barhanin et al, 1996 ). In this case the KCNE1 protein interacts with the voltage-sensor domain and slows channel opening ( Nakajo and Kubo, 2007 ; Abbott, 2022 ). However, Kv7.1 also associates with KCNE2 and KCNE3 in epithelial cells and here the channel loses time-dependent properties as the voltage-sensor becomes locked by the interleaving of the KCNE proteins ( Abbott, 2022 ).…”

A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking

“…For example, the α-subunits of the voltage-gated L-type calcium channel (Ca v 1.1-1.4) co-assemble with α2δ, β and/or γ subunits (5, 6). The homotetrameric α-subunits of the voltage-gated potassium channel K v 4.2 can further complex with KChIP1 and DPP6S as dodecamer (7, 8). Proper assembly of such ion channel complexes is crucial for cellular homeostasis and strictly regulated to achieve appropriate channel density and function in the plasma membrane (1).…”

Medicinal plant rosemary relaxes blood vessels by activating vascular smooth muscle KCNQ channels

“…1,2 In addition to heteromultimerization within the same subfamily (e.g., KCNQ2/3, KCNQ4/5), the functional repertoire of KCNQ channels (as subsequently also discovered for other Kv channels) is expanded by co-assembly with single transmembrane segment KCNE regulatory subunits. 3 In vascular smooth muscle, KCNQ4 and KCNQ5 can heteromultimerize, 4,5 together with KCNE4, 6,7 to form functional channels that control the resting membrane potential and facilitate vasodilatations elicited by certain receptors, e.g., β adrenoceptors and calcitonin gene-related peptide receptors. 5,[7][8][9][10][11][12] Nearly all the work involving vascular KCNQ channels has been performed in male rodents; however, vascular KCNQ channel expression and function were recently revealed to be estrogen-dependent, manifesting as the potency of certain KCNQ-specific activators shifting by >10fold when comparing female rats from different estrus phases (high versus low estrogen levels).…”

“…Voltage‐gated potassium (Kv) channels in the KCNQ (Kv7) subfamily serve a number of diverse and essential roles in physiology, ranging from action potential repolarization in the heart to K + recycling in the gastric epithelium and inner ear (KCNQ1), neuronal action potential gatekeeping (KCNQ2/3) and regulation of vascular tone (KCNQ4/5) 1,2 . In addition to heteromultimerization within the same subfamily (e.g., KCNQ2/3, KCNQ4/5), the functional repertoire of KCNQ channels (as subsequently also discovered for other Kv channels) is expanded by co‐assembly with single transmembrane segment KCNE regulatory subunits 3 …”