An overview of trafficking and assembly of neurotransmitter receptors and ion channels (Review)

Abstract

Ionotropic neurotransmitter receptors and voltage-gated ion channels assemble from several homologous and non-homologous subunits. Assembly of these multimeric membrane proteins is a tightly controlled process subject to primary and secondary quality control mechanisms. An assembly pathway involving a dimerization of dimers has been demonstrated for a voltage-gated potassium channel and for different types of glutamate receptors. While many novel C-terminal assembly domains have been identified in various members of the voltage-gated cation channel superfamily, the assembly pathways followed by these proteins remain largely elusive. Recent progress on the recognition of polar residues in the transmembrane segments of membrane proteins by the retrieval factor Rer1 is likely to be relevant for the further investigation of trafficking defects in channelopathies. This mechanism might also contribute to controlling the assembly of ion channels by retrieving unassembled subunits to the endoplasmic reticulum. The endoplasmic reticulum is a metabolic compartment studded with small molecule transporters. This environment provides ligands that have recently been shown to act as pharmacological chaperones in the biogenesis of ligand-gated ion channels. Future progress depends on the improvement of tools, in particular the antibodies used by the field, and the continued exploitation of genetically tractable model organisms in screens and physiological experiments.

Characterization of the Oligomeric Structure of the Ca2+-activated Cl− Channel Ano1/TMEM16A

“…With the possible exception of Ano8 and Ano10, anoctamins are also predicted to have a re-entrant loop between transmembrane domains 5 and 6 that may contribute toward Cl Ϫ selectivity (21,22). A common property of ion channels is their oligomeric nature, which may be homo-or hetero-oligomeric (23). For example, activation of the MthKCa 2ϩ -activated K ϩ channel from Methanobacterium thermoautrophicum involves oligomerization of 4 subunits (24) and it has been suggested that the mammalian Maxi-K K ϩ channel is activated by a similar mechanism (25).…”

Dual-color quantum dot detection of a heterotetrameric potassium channel (hKCa3.1)

“…It has been reported that tetrameric K ϩ channels are structurally composed by two dimers of dimers (15,29,31) and functionally activated through dimerization of the COOHterminal tails of two channel subunits (35). Molecular dynamics simulations further suggest that tetrameric inwardly rectifying potassium channels K ir 3.1 and K ir 6.2 undergo a transition from tetrameric to a dimer-of-dimers symmetry, playing a role in channel gating (5).…”

Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways: Therapeutic Effects

“…(B) Possible inside-out mechanisms, resulting from intracellular binding to nascent NMDA receptors. Existing data show that ligands can act as pharmacological chaperones for glutamate receptors within the ER (96), analogous to experiments in which nicotine acts as a pharmacological chaperone for nicotinic acetylcholine receptors. Two possible sequelae could lead to increased BDNF secretion.…”