Abstract
Kv7.2 and Kv7.3 are the main components of the neuronal voltage-dependent M-current, which is a subthreshold potassium conductance that exerts an important control on neuronal excitability. Despite their predominantly intracellular distribution, these channels must reach the plasma membrane in order to control neuronal activity. Thus, we analyzed the amino acid sequence of Kv7.2 to identify intrinsic signals that may control its surface expression. Removal of the interlinker connecting helix A and helix B of the intracellular C-terminus produces a large increase in the number of functional channels at the plasma membrane. Moreover, elimination of this linker increased the steady-state amount of protein, which was not associated with a decrease of protein degradation. The magnitude of this increase was inversely correlated with the number of helix A – helix B linkers present in the tetrameric channel assemblies. In contrast to the remarkable effect on the amount of Kv7.2 protein, removal of the Kv7.2 linker had no detectable impact on the steady-state levels of Kv7.3 protein.
Highlights
Kv7 (KCNQ) channels are of crucial importance in excitable tissues [1.2]
CaM binds to helix A and B of the intracellular C-terminus [14,15,16], and some mutations linked to Benign Familial Neonatal Convulsions (BFNC) that are located in helix A [17,18] reduce CaM binding, thereby leading to ER retention and the consequent reduction in surface expression [13,19]
A systematic evaluation of Kv7.2 C-terminal deletion constructs in Xenopus oocytes revealed a remarkable effect of the linker between helices A and B on surface expression (Fig. 1A), which could be measured using an extracellular HA epitope tag located between S1–S2 [10,11]
Summary
Kv7 (KCNQ) channels are of crucial importance in excitable tissues [1.2]. In the nervous system, Kv7.2 and Kv7.3 are the main components of the M-current, a voltage-dependent, noninactivating K+ current that plays a fundamental role in controlling the activity of both peripheral and central neurons [3]. A membrane protein must pass through multiple quality control mechanisms before reaching the plasma surface that begin with the translation of the protein and that involve subunit assembly, ER exit, transport to the membrane and their maintenance therein, endocytosis and degradation [7,8]. These overlapping events control ion channel expression at the cell surface and may be coordinated or even cooperate [7]. CaM binds to helix A and B of the intracellular C-terminus [14,15,16], and some mutations linked to BFNC that are located in helix A [17,18] reduce CaM binding, thereby leading to ER retention and the consequent reduction in surface expression [13,19]
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