Physiologic and pathophysiologic consequences of altered sialylation and glycosylation on ion channel function

Abstract

Voltage-gated ion channels are transmembrane proteins that regulate electrical excitability in cells and are essential components of the electrically active tissues of nerves, muscle and the heart. Potassium channels are one of the largest subfamilies of voltage sensitive channels and are among the most-studied of the voltage-gated ion channels. Voltage-gated channels can be glycosylated and changes in the glycosylation pattern can affect ion channel function, leading to neurological and neuromuscular disorders and congenital disorders of glycosylation (CDG). Alterations in glycosylation can also be acquired and appear to play a role in development and aging. Recent studies have focused on the impact of glycosylation and sialylation on ion channels, particularly for voltage-gated potassium and sodium channels. The terminal step of sialylation often affects channel activation and inactivation kinetics. The presence of sialic acids on O or N-glycans can alter the gating mechanism and cause conformational changes in the voltage-sensing domains due to sialic acid's negative charges. This manuscript will provide an overview of sialic acids, potassium and sodium channel function, and the impact of sialylation on channel activation and deactivation.

Keywords: Congenital disorders of glycosylation; Glycosylation; Neurological disorders; Sialylation; Voltage-gated potassium channels; Voltage-gated sodium channels.

Fig. 1

Types of sialic acids.

Fig. 2

Sialylation pathway in mammals.

Fig. 3

Topology of a kV channel subunit. The sialylation sites specific to 2 N-glycosylation sites between S1 and S2 linker are shown. Other glycosylation sites can also appear on the S3–S4 linker (not shown here).

Fig. 4

An action potential generated by the model of Hodgkin and Huxley in response to application of a steady depolarizing current. In response to this depolarizing current, the voltage-gated Na⁺ channel permits conductance of Na⁺ through the channel along its concentration gradient. Once the voltage-gated Na⁺ channel begins to inactivate, the voltage-gated K⁺ channel increases its conductance, permitting efflux of K⁺ to return the membrane potential to its rest level (0 volts). Membrane potential is given in black, Na conductance is in red and K conductance is in green. There is a horizontal line at the resting membrane potential of 0 volts. Ionic currents are the product of the membrane potential (shown) minus the reversal potential (positive for Na and negative for K, given by the corresponding Nernst potentials) times the conductance (shown).