Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel

Abstract

being substituted by either a leucine (R271L) or a glutgated ion channel receptors, culminating in opening amine (R271Q) (Shiang et al., 1993). R271 lies at the of the integral ion channel pore. Human hereditary external vestibule of the ion channel pore and forms part hyperekplexia, or startle disease, is caused by mutations of the extracellular loop linking the second and third in both the intracellular or extracellular loops flanking membrane-spanning domains (the M2-M3 loop). The the pore-lining M2 domain of the glycine receptor α1 physiological effect of these mutations is to reduce the subunit. These flanking domains are designated the glycine efficacy and single channel conductance of recom-M1-M2 loop and the M2-M3 loop respectively. We binant homomeric and heteromeric GlyRs (Langosch et al., show that four startle disease mutations and six addi-1994; Rajendra et al., 1994Rajendra et al., , 1995a. In addition, both tional alanine substitution mutations distributed mutations converted β-alanine and taurine from full agonthroughout both loops result in uncoupling of the ists into competitive antagonists without dramatically ligand binding sites from the channel activation gate.affecting their binding affinities (Laube et al., 1995; We therefore conclude that the M1-M2 and M2-M3 Rajendra et al., 1995a). As these results are consistent loops act in parallel to activate the channel. Their with an uncoupling of the agonist binding process from locations strongly suggest that they act as hinges the channel activation gate, it was concluded that R271 governing allosteric control of the M2 domain. As the formed a crucial component of the allosteric signal transmembers of the ligand-gated ion channel superfamily duction pathway (Langosch et al., 1994; Rajendra et al., share a common structure, this signal transduction 1994, 1995aLynch et al., 1995). model may apply to all members of this superfamily.Additional startle disease mutations have recently been Keywords: β-alanine/glycine/ligand-gated ion channel identified in the M2-M3 loop (Y279C, Shiang et al., superfamily/signal transduction/taurine 1995; K276E, Elmslie et al., 1996) and in the intracellular M1-M2 loop (I244N, Rees et al., 1995). We show here that the Y279C and K276E mutations, like the R271L

New Hyperekplexia Mutations Provide Insight into Glycine Receptor Assembly, Trafficking, and Activation Mechanisms

“…Consistent with previous studies (10,(37)(38)(39)(40), dominant mutations were expressed at the cell surface, thereby causing changes to the glycine sensitivity, conductance, and/or open probability. In contrast, recessive and compound heterozygous mutations mainly affected cell surface trafficking and insertion of receptors into the membrane (10,(41)(42)(43).…”

Fixation of allosteric states of the nicotinic acetylcholine receptor by chemical cross-linking

“…A lot of conserved lysine residues are indeed located in the receptor's extracellular part-in the region between the agonist-binding site and the ion channel. This region (especially the M2-M3 loop) has been shown to be rather important for the coupling between ligand binding and channel gating for different members of the family of ligand-gated ion channels (34)(35)(36).…”

Taurine blunts LPS-induced increases in intracellular calcium and TNF-α production by Kupffer cells

“…Glycine inhibits fast synaptic neurotransmission in the central nervous system by acting on the post-synaptic membrane on a specific receptor belonging to the ligand-gated ion channel superfamily [43]. Taurine is an endogenous agonist for this strychnine-sensitive glycine receptor [25] increasing chloride conductance leading to chloride influx and hyperpolarizing the membrane [26,44].…”