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The Neuromuscular Junction
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
Other forms of nicotinic ACh receptors are found in other parts of the nervous system. Parasympathetic postganglionic neurons have ACh receptors that consist of two α3 and three β4 subunits. There are also nicotinic ACh receptors in the brain consisting of different types of α and β subunits, or of α subunits only (pentameric homomers), the latter having an appreciable permeability to Ca2+ in addition to Na+ and K+. The other type of ACh receptor is the muscarinic type, because the alkaloid muscarine, a toxin derived from a species of poisonous mushrooms, acts as an ACh agonist at these receptors. Found in the CNS, these receptors are coupled to G proteins (Section 6.3) and differ in structure from nicotinic ACh receptors.
Behavioural pharmacology
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
SL 651498 is structurally related to the β-carbolines, and, like these, has higher affinity for al-containing receptors than for α2- or α3-containing receptors. Like zolpidem, its affinity for α5-containing receptors is an order of magnitude lower. It behaves as a full agonist atα2- or α3-containing receptors, and as a partial agonist at α1- and α5-containing receptors. The behavioural properties of SL 651498 have been described extensively. SL 651498 releases punished responding in a rat conflict model, and has potent anxiolytic activity in the elevated plus-maze, the four-plate test and the light-dark box (Figure 6.15). It has potent anticonvulsant activity against pentylenetetrazole-evoked seizures, is less active towards isoniazid-evoked seizures and is inefficacious towards maximal electroshock. This is very similar to the anticonvulsant spectrum of non-specific partial agonists described above. In tests of sedative or myo-relaxant activity (rotarod and horizontal wire), SL 651498 shows some impairment of performance, but only at doses some 10-fold higher than anxiolytic doses. Acute or chronic administration of SL 651498 produced only minor changes to the EEG.
Major histocompatibility complex
Published in Gabriel Virella, Medical Immunology, 2019
Ellen Klohe, Janardan P. Pandey
The HLA class I heterodimers are formed by a 43,000–48,000 dalton α-chain encoded by the different alleles at the HLA-A, HLA-B, and HLA-C loci paired with β2-microglobulin, a 12,000 dalton protein encoded by a minimally polymorphic, non-HLA gene located on chromosome 15. The α-chain has a long extracellular region folded into three (α1, α2, and α3) domains, as well as transmembrane and intracellular segments. β2-microglobulin forms a single immunoglobulin-type domain that is noncovalently associated with the α-chain.
Therapeutic potential of GABAA receptor subunit expression abnormalities in fragile X syndrome
Published in Expert Review of Precision Medicine and Drug Development, 2022
Mathijs B. van der Lei, R. Frank Kooy
From these experiments, it was concluded that the α1 subunits of the GABAA receptor are responsible for the sedative side effects of classical benzodiazepines; meanwhile, the anxiolytic effects seem to be predominantly mediated by the α2 and partially by α3 subunits of the GABAA receptor, and the α5 subunits of the GABAA receptors seem to play a role in cognition and learning. Based on these elegant molecular genetic studies with transgenic subunit and point-mutated mice the development of compounds targeting the α2, α3 or the α5 subunits rather than α1 subunit of the GABAA receptor were initiated. As previously discussed, juvenile Fmr1 KO mice have especially a decreased mRNA and protein expression of the α2 subunit of the GABAA receptor in the cortex, cerebellum and hippocampus. Positive allosteric modulation of this specific subunit could therefore be potentially relevant for treatment, also because anxiolytic effects seem to be mediated by the α2 subunit (together with the α3 subunit), and increased anxiety is one of the key behavioral phenotypes observed in fragile X syndrome [54]. Therefore, the following sections will discuss the current available positive allosteric modulators of the α2/3 subunits of the GABAA receptor.
Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation
Published in Fetal and Pediatric Pathology, 2021
Alyssa Kalsbeek, Renee Dhar-Dass, Abdul Hanan, Eman Al-Haddad, Iman William, Adina Alazraki, Janet Poulik, Kasey McCollum, Aya Almashad, Bahig M. Shehata
In this study, we found mutations of the α3 and β4 AChR subunit on chromosome 15q24 in four cases as well as a novel missense mutation of ATP2B4 on Chromosome 1q32 in the fifth case. The gene mutations involving the acetylcholine receptor and the plasma membrane calcium ATPase resulted in visceral myopathy, since both are involved in smooth muscle function which is thought to be an underlying cause of MMIHS. This includes genes that have been reported by Halim et al. and Gamboa et al. such as muscle associated genes for actin gamma 2 (ACTG2) a smooth muscle contractile gene, myosin heavy chain 11 (MYH11), leimodin 1 (LMOD1), myosin light chain kinase (MYLK), and myosin regulatory light chain 9 (MYL9) [5,9,10]. Mutations in the CHRNA3 and CHRNB4 genes in MMIHS have not been well studied. While other missense mutations associated with MMIHS have been reported, such as the mutation of ACTG2 reported by Halim et al, there have been no reports of a missense mutation of the ATP2B4 gene [10]. A study by Billon et al. also identified a novel gene candidate, PDCL3, associated with MMIHS. PDCL3 encodes a protein that helps with actin folding via chaperone protein CCT which impacts the contractility of smooth muscle tissue [11].
Ultrastructural and immunofluorescence analysis of anterior lens capsules in autosomal recessive Alport syndrome
Published in Ophthalmic Genetics, 2021
Jiayue Zhou, Jing Wu, Qichuan Yin, Xiaoning Yu, Yilei Cui, Hao Yang, Xingchao Shentu
Mutations in the COL4A3, COL4A4 (6), and COL4A5 (7) genes encoding α3, α4, and α5 chains of type Ⅳ collagen, respectively, are responsible for the Alport syndrome. There are six different types of collagen α chains forming three forms of type Ⅳ collagen heterotrimers (8). The heterotrimers comprised of α1(Ⅳ)/α1(Ⅳ)/α2(Ⅳ), α3(Ⅳ)/α4(Ⅳ)/α5(Ⅳ), and α5(Ⅳ)/α5(Ⅳ)/α6(Ⅳ) then form distinct type Ⅳ collagen networks in basement membranes (8). The α1(Ⅳ)/α1(Ⅳ)/α2(Ⅳ) network is the most widespread basement membrane component (9), whereas the α3(Ⅳ)/α4(Ⅳ)/α5(Ⅳ) network is mainly distributed in adult glomerular basement membrane, cochlea (stria vascularis), cornea (Descemet’s and Bowman’s membranes), lens capsule, and retina (inner limiting membrane and Bruch’s membrane). The α5(Ⅳ)/α5(Ⅳ)/α6(Ⅳ) network exists in skin (10). According to the inheritance pattern and mutated genes, the syndrome can be divided into three types: approximately 80%-85% of cases are classified as X-linked Alport syndrome 1 (XLAS) caused by COL4A5 mutations, 10%-15% are classified as autosomal recessive Alport syndrome 2 (ARAS) caused by COL4A3 or COL4A4 mutations, and less than 5% are classified as autosomal dominant Alport syndrome 3 (ADAS) caused by COL4A3 mutations (11).