Structure and function of an acetylcholine receptor

Kistler, Joerg; Stroud, Robert M.; Klymkowsky, Michael W.; Lalancette, Roger A.; Fairclough, Robert H.

doi:10.1016/s0006-3495(82)84685-7

Cited by 280 publications

(140 citation statements)

References 57 publications

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“…Of special interest is the doughnut appearance seen under the mildest negative staining conditions. This appearance is strongly reminiscent of enface views of the two other ion conducting channels well characterized in negative stain: the gap junction structure (19), and the nicotinic acetylcholine receptor (8). In both of these instances the proteins form structures of 85-90 A diam with prominent, dark staining central pits, interpreted to be associated with the ionic pores .…”

Section: Ellisman Et Almentioning

confidence: 76%

“…An orientation with the long axis normal to the membrane might be more likely, but the l70-Á length far exceeds the bilayer thickness . By comparison, the nicotinic acetylcholine receptor is only 110 A in total length, a length nevertheless sufficient to extend some 50 A into the extracellular medium (8). Therefore, we undertook studies to resolve this point, using the techniques of freezefracture and freeze-etching on Na' channel reconstituted into vesicles and additional negative staining procedures on solubilized protein.…”

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confidence: 99%

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Molecular morphology of the tetrodotoxin-binding sodium channel protein from Electrophorus electricus in solubilized and reconstituted preparations.

Ellisman

Miller

Agnew³

1983

The Journal of Cell Biology

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The appearance of detergent-solubilized voltage-regulated sodium channel protein was recently characterized by this laboratory. Negative-staining revealed rod-shaped particles measuring 40 X 170 A. Further studies have suggested that the actual configuration of this protein may be quite different from the rod-shaped structures. Freeze-fracture and freeze-etch images of the protein in reconstituted membranes indicated that the channel is cylindrical with a diameter of 100 A and a minimum length of 80 A. Experiments with two detergent systems (Lubrol-PX and sodium cholate) enabled us to explain the discrepancy between this structure and the rod-shaped particles visualized earlier. Negative staining in either detergent at low pH (4.5) produced rod-shaped structures. As the pH was increased, doughnut-shaped particles, consistent with the structure of the protein in freeze-etch, appeared in negative stain. The tendency of the protein to change shape under different pH conditions appears to be a peculiar property of this protein.

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Section: Ellisman Et Almentioning

confidence: 76%

mentioning

confidence: 99%

Molecular morphology of the tetrodotoxin-binding sodium channel protein from Electrophorus electricus in solubilized and reconstituted preparations.

Ellisman

Miller

Agnew³

1983

The Journal of Cell Biology

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“…It is a reasonable hypothesis, based on the appearance of the negatively stained receptor (27,28), that in the mature AcChoR complex, each of the subunits borders the ion channel. By analogy to the case of the well-characterized alamethicin channel (29), the ionophore boundary surfaces of the subunits are likely to contain polar (or charged) regions of the protein helix.…”

Section: Methodsmentioning

confidence: 99%

Identification of homo-oligomers as potential intermediates in acetylcholine receptor subunit assembly.

Anderson¹,

Blobel²

1983

Proc. Natl. Acad. Sci. U.S.A.

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We have examined the sedimentation behavior, on sucrose density gradients, of acetylcholine receptor (AcChoR) subunits synthesized in vitro and integrated into heterologous rough microsomal membranes. In media containing nondenaturing detergents such as Triton X-100 or deoxycholate, the subunits appear to self-associate although, as previously reported, no heterologous interactions were detected. The sedimentation profiles assume a broad distribution in the region of 7-13 S. However, the peak fractions occupy the same region of the gradient as does native AcChoR, run in parallel. Such large homo-oligomers were not observed for another membrane protein, opsin, studied in the same way. This indicated that the associations are indeed between the AcChoR subunits and not simply between all newly synthesized membrane proteins. The homologous associations are interpreted to suggest a mechanism for maintaining the ionophore surfaces of the subunits in an energetically preferred, but metastable, configuration during the lengthy period of post-translational assembly.The oligomeric assembly of the acetylcholine receptor (AcChoR) subunits poses a unique problem in membrane protein biogenesis-that is, how four distinct transmembrane glycoproteins, translated from separate mRNAs (1), are assembled into a quaternary complex that forms a hydrophilic ion channel through the lipid bilayer. The problem is further complicated by the observation that AcChoR subunit assembly does not occur immediately upon insertion of the subunits into the rough endoplasmic reticulum (RER) membrane (1) but rather after a delay of at least 30 min, or perhaps even longer (2). This fact implies that (i) newly synthesized AcChoR subunits must be transported to a common subcellular site, perhaps the Golgi apparatus (2, 3), for assembly to occur, and (ii) the individual subunits must assume a stable configuration in the lipid bilayer of intracellular organelles, for a considerable time prior to formation of the ionophore complex.The AcChoR subunits are comprised by four polypeptidesa, ,3, y, and 6, of apparent molecular masses of 40, 50, 60, and 65 kilodaltons (kDa), respectively (4). Their stoichiometry in the mature complex is a2Py8 (5-7). These subunits are synthesized with signal sequences (8-10) and are cotranslationally integrated into the RER membrane (1) by a mechanism that utilizes the recently purified (11, 12) signal recognition particle (8). Although these subunits are not associated with one another at this stage in their biosynthesis (1), they exhibit a transmembrane topology that is similar, at least in its gross aspects, to that observed for their counterparts in the mature hetero-oligomer (13,14).In this study we have examined the sedimentation behavior of these early biosynthetic forms of the AcChoR subunits on sucrose density gradients. The subunits each appear to self-associate, forming homo-oligomers in the range of 7-13 S. Such homologous associations were not observed for another membrane protein, opsin, studied in an ident...

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“…Peptide hormones (e.g., Melatonin, 35 Glucagon), Proteins: Growth factors (e.g., Epidermal growth factor, 36 Platelet derived growth factor), Steroids (e.g., Testosterone, 37 Estrogen, Progestirone, Carticosteroids), Retenoids -Synthesised from vit-A, Neurotrophins (e.g., Nerve growth factor), 38 Neuropeptids (e.g., Enkephalins and Endorphins), 39 Small gases (e.g., Nitric oxide), extra-cellular matrix components (e.g.,Fibronectin), 40 Neurotransmittors (e.g., Acetylcholine, Dopamine, 41 Adrenaline,5-HT, 42 Histamine, GABA, Glutamate), Ecosanoids (e.g., Prostaglandins, Thromboxanes, Prostacyclines), Leukotrienes, Vitamines (e.g., Vit-D3), cytokines (e.g., Interferon-gamma), 43 Chemokines (e.g., RANTES), 44 Amino acid derivatives (e.g., epinephrine), 44 Poly peptides (e.g., Insulin), 45 Fatty acid derivatives.…”

Section: These Molecules Have Been Functionally Classified Asmentioning

confidence: 99%

Role of GPCRs towards Cell: An explanation of G-Protein Coupled Receptor Structure

Raj¹

2017

JSRT

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G-protein coupled receptors are the heptahelical, serpentine receptor and are multifunctional receptors having modulatory activity of a wide variety of biological process including: Neurotransmission, Chemoattraction, Cardiac function, Olfaction and Vision etc. At largest level they are involved in signal transduction across cell membranes therefore they represent major targets in the development of novel drug candidates in all clinical areas. Particularly membrane cholesterol has been reported to have a great role in the functioning of a number of GPCRs. Apart from this it also have some drawbacks. Mutations that occur are associated with a broad spectrum of diseases of diverse etiology. As a mutations result, there is a change in receptor activity (GPCR become inactive, overactive, or constitutively active), in the process of ligand binding and signal transduction. Changes in the GPCRs functioning can cause diseases such as retinitis pigmentosa (rhodopsin mutations), nephrogenic diabetes insipidus (vasopressin receptor mutations), and obesity (melanocortin receptor mutations). Keywords Brief introduction of 'G' ProteinG-Protein is composed of 3 subunits alpha, beta and gaama. These G-Protein binds to the Guanosine Triphosphate (GTP) present in the receptor. Alpha and gaama subunits are linked to membrane by covalently attached lipids. The alpha subunits associate to GPCRs only when in GDP mode. G-Proteins in inactive state bound to the GDP then it moves and get bound to the GTP then after binding it gets activated. Alpha subunit of G-Protein has GTPase activity. Discovery, detection of GPCRsAs we know that the molecular properties of 7 TM receptors has been discovered over the past 40 years. However, rhodopsin had been identified as a photosensitive pigment as early as the 1870s, and its covalent ligand retinal was reported in 1933.9 From the century ago we know about the ligand-activated receptors, in these receptors reactive cells act as a 'receptive substance' on the surface.10,11 Early experiments with tissue preparations measured the responses to stimulators (agonists) and inhibitors (antagonists). 12There are so many signalling compounds present inside the cells. These include the second messenger cyclic AMP (cAMP) and the enzyme adenylyl cyclase (; 13 Nobel Prize in Physiology or Medicine 1971 to Earl W. Sutherland, Jr.), cAMP-dependent protein kinase 14 and heterotrimeric G-proteins, [15][16][17] Nobel Prize in Physiology or Medicine 1994 to Martin Rodbell and Alfred G. Gilman).The nature of the ligand-activated receptors remained controversial up to the 1970s. Epinephrine is an important hormone and neurotransmitter that influences many different physiological processes, e.g. regulation of heart rate and blood pressure. Cells responsive to epinephrine have specific plasma membrane receptors (adrenergic receptors) that interact with the hormone. There are at least nine different adrenergic receptors, grouped as α-and β-receptors. Different tissues and organs respond in different manners to...

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Structure and function of an acetylcholine receptor

Cited by 280 publications

References 57 publications

Molecular morphology of the tetrodotoxin-binding sodium channel protein from Electrophorus electricus in solubilized and reconstituted preparations.

Molecular morphology of the tetrodotoxin-binding sodium channel protein from Electrophorus electricus in solubilized and reconstituted preparations.

Identification of homo-oligomers as potential intermediates in acetylcholine receptor subunit assembly.

Role of GPCRs towards Cell: An explanation of G-Protein Coupled Receptor Structure

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