The Startle Disease Mutation Q266H, in the Second Transmembrane Domain of the Human Glycine Receptor, Impairs Channel Gating

1999 ◽  
Vol 55 (2) ◽  
pp. 386-395 ◽  
Author(s):  
Andrew J. Moorhouse ◽  
Patrice Jacques ◽  
Peter H. Barry ◽  
Peter R. Schofield
Keyword(s):  
Transmembrane Domain ◽  
Glycine Receptor ◽  
Channel Gating ◽  
Disease Mutation ◽  
Startle Disease

scholarly journals The K276E Startle Disease Mutation in the Glycine Receptor: Effects on Channel Gating

2011 ◽  
Vol 100 (3) ◽  
pp. 433a
Author(s):  
Mirko Moroni ◽  
Remigijus Lape ◽  
David Colquhoun ◽  
Andrew J.R. Plested ◽  
Lucia G. Sivilotti
Keyword(s):  
Glycine Receptor ◽  
Channel Gating ◽  
Disease Mutation ◽  
Startle Disease

scholarly journals Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor.

1994 ◽  
Vol 269 (29) ◽  
pp. 18739-18742
Author(s):  
S. Rajendra ◽  
J.W. Lynch ◽  
K.D. Pierce ◽  
C.R. French ◽  
P.H. Barry ◽  
...  
Keyword(s):  
Glycine Receptor ◽  
Startle Disease ◽  
Disease Mutations

scholarly journals A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition

2020 ◽  
Vol 40 (25) ◽  
pp. 4954-4969 ◽  
Author(s):  
Georg Langlhofer ◽  
Natascha Schaefer ◽  
Hans M. Maric ◽  
Angelo Keramidas ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Glycine Receptor ◽  
Startle Disease ◽  
Glycinergic Inhibition

scholarly journals Regulation of Bestrophin Cl Channels by Calcium: Role of the C Terminus

2008 ◽  
Vol 132 (6) ◽  
pp. 681-692 ◽  
Author(s):  
Qinghuan Xiao ◽  
Andrew Prussia ◽  
Kuai Yu ◽  
Yuan-yuan Cui ◽  
H. Criss Hartzell
Keyword(s):  
Amino Acids ◽  
Density Functional ◽  
Transmembrane Domain ◽  
Channel Gating ◽  
Regulatory Domain ◽  
Acidic Amino Acids ◽  
C Terminus ◽  
Ef Hand ◽  
Cl Channels

Human bestrophin-1 (hBest1), which is genetically linked to several kinds of retinopathy and macular degeneration in both humans and dogs, is the founding member of a family of Cl− ion channels that are activated by intracellular Ca2+. At present, the structures and mechanisms responsible for Ca2+ sensing remain unknown. Here, we have used a combination of molecular modeling, density functional–binding energy calculations, mutagenesis, and patch clamp to identify the regions of hBest1 involved in Ca2+ sensing. We identified a cluster of a five contiguous acidic amino acids in the C terminus immediately after the last transmembrane domain, followed by an EF hand and another regulatory domain that are essential for Ca2+ sensing by hBest1. The cluster of five amino acids (293–308) is crucial for normal channel gating by Ca2+ because all but two of the 35 mutations we made in this region rendered the channel incapable of being activated by Ca2+. Using homology models built on the crystal structure of calmodulin (CaM), an EF hand (EF1) was identified in hBest1. EF1 was predicted to bind Ca2+ with a slightly higher affinity than the third EF hand of CaM and lower affinity than the second EF hand of troponin C. As predicted by the model, the D312G mutation in the putative Ca2+-binding loop (312–323) reduced the apparent Ca2+ affinity by 20-fold. In addition, the D312G and D323N mutations abolished Ca2+-dependent rundown of the current. Furthermore, analysis of truncation mutants of hBest1 identified a domain adjacent to EF1 that is rich in acidic amino acids (350–390) that is required for Ca2+ activation and plays a role in current rundown. These experiments identify a region of hBest1 (312–323) that is involved in the gating of hBest1 by Ca2+ and suggest a model in which Ca2+ binding to EF1 activates the channel in a process that requires the acidic domain (293–308) and another regulatory domain (350–390). Many of the ∼100 disease-causing mutations in hBest1 are located in this region that we have implicated in Ca2+ sensing, suggesting that these mutations disrupt hBest1 channel gating by Ca2+.

scholarly journals KCNE3 Truncation Mutants Reveal a Bipartite Modulation of KCNQ1 K+ Channels

2004 ◽  
Vol 124 (6) ◽  
pp. 759-771 ◽  
Author(s):  
Steven D. Gage ◽  
William R. Kobertz
Keyword(s):  
Amino Acids ◽  
Transmembrane Domain ◽  
Channel Gating ◽  
Terminal Region ◽  
Type I ◽  
Long Qt ◽  
Transmembrane Peptides ◽  
K Channels ◽  
Voltage Gated ◽  
La Luna

The five KCNE genes encode a family of type I transmembrane peptides that assemble with KCNQ1 and other voltage-gated K+ channels, resulting in potassium conducting complexes with varied channel-gating properties. It has been recently proposed that a triplet of amino acids within the transmembrane domain of KCNE1 and KCNE3 confers modulation specificity to the peptide, since swapping of these three residues essentially converts the recipient KCNE into the donor (Melman, Y.F., A. Domenech, S. de la Luna, and T.V. McDonald. 2001. J. Biol. Chem. 276:6439–6444). However, these results are in stark contrast with earlier KCNE1 deletion studies, which demonstrated that a COOH-terminal region, highly conserved between KCNE1 and KCNE3, was responsible for KCNE1 modulation of KCNQ1 (Tapper, A.R., and A.L. George. 2000 J. Gen. Physiol. 116:379–389.). To ascertain whether KCNE3 peptides behave similarly to KCNE1, we examined a panel of NH2- and COOH-terminal KCNE3 truncation mutants to directly determine the regions required for assembly with and modulation of KCNQ1 channels. Truncations lacking the majority of their NH2 terminus, COOH terminus, or mutants harboring both truncations gave rise to KCNQ1 channel complexes with basal activation, a hallmark of KCNE3 modulation. These results demonstrate that the KCNE3 transmembrane domain is sufficient for assembly with and modulation of KCNQ1 channels and suggests a bipartite model for KCNQ1 modulation by KCNE1 and KCNE3 subunits. In this model, the KCNE3 transmembrane domain is active in modulation and overrides the COOH terminus' contribution, whereas the KCNE1 transmembrane domain is passive and reveals COOH-terminal modulation of KCNQ1 channels. We furthermore test the validity of this model by using the active KCNE3 transmembrane domain to functionally rescue a nonconducting, yet assembly and trafficking competent, long QT mutation located in the conserved COOH-terminal region of KCNE1.

Molecular mechanisms of glycine transporter GlyT2 mutations in startle disease

2012 ◽  
Vol 393 (4) ◽  
pp. 283-289 ◽  
Author(s):  
Victoria M. James ◽  
Jennifer L. Gill ◽  
Maya Topf ◽  
Robert J. Harvey
Keyword(s):  
Startle Response ◽  
Molecular Mechanisms ◽  
Glycine Receptor ◽  
Welfare Impacts ◽  
Startle Disease ◽  
Glycine Transporter ◽  
Tactile Stimuli ◽  
Genes Encoding ◽  
Muscle Hypertonia ◽  
Α1 Subunit

Abstract Startle disease affects newborn children and involves an exaggerated startle response and muscle hypertonia in response to acoustic or tactile stimuli. The primary cause of startle disease is defective inhibitory glycinergic transmission due to mutations in the postsynaptic glycine receptor (GlyR) α1 subunit gene (GLRA1). However, mutations have also been discovered in the genes encoding the GlyR β subunit (GLRB) and the presynaptic glycine transporter GlyT2 (SLC6A5). GlyT2 mutations have also been detected in Belgian Blue cattle and Irish Wolfhounds, where they have significant economic and animal welfare impacts.

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