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Comparative Anatomy and Physiology of the Mammalian Eye
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
There is a steady dark current that flows along the length of the photoreceptors. This current is maintained by Na+ which is extruded from the inner segment by a Na+-K+-ATPase pump and then enters passively through Na+ channels in the outer segment.129,135 Thus, during darkness, the photoreceptors are continuously discharging. Exposure to light results in the closure of the Na+ channels in the outer segment and a resultant hyperpolarization and a decrease in the release of neurotransmitter. This process is termed transduction and involves the absorption of a photon by rhodopsin. This, in turn, communicates via a molecule termed transducin to activate the enzyme phosphodiesterase which will hydrolyze many cyclic GMP molecules which are responsible for maintaining the Na+ channels.129 It is this phosphodiesterase enzyme that has been found to be abnormal in animals, such as the Irish Setter and Collie dogs and the Rd mouse, that undergo hereditary retinal degeneration. The signal from the photoreceptor cell is transmitted inwards to the ganglion cells via the bipolar cell with input from the horizontal and amacrine cell. The neurotransmitters involved in this process may include GABA, glycine, acetylcholine, monoamines, peptides, substance-P, aspartate, and glutamate.136,137
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The receptors for dopamine (DA) were first recognized by their biological activities, radioligand-binding analyses, and the empirical rank order of actions of agonists and antagonists [1]. In the early 1970s, two types of DA receptors (DARs) were identified: those that were positively coupled to adenylate cyclase (AC) and increased cAMP production, and those that were negatively coupled to AC and reduced intracellular cAMP levels [2]. Progress with molecular cloning techniques in the 1980s led to the cloning of the rhodopsin and β2 adrenergic receptors, both of which were characterized as seven transmembrane domain (7TM) receptors. The rhodopsin receptor transmits light signals from the retina to the brain through interaction with a G protein known as transducin, while the β2 adrenergic receptors bind norepinephrine (NE) and epinephrine (Epi) and interact with another G protein, known as G stimulatory or Gs. Elucidation of the 7TM architecture, as well as the establishment of the functional linkage of these receptors to the family of G proteins, prompted an extensive search for similar receptors. Many receptors were eventually identified, and subsequently became known as G protein-coupled receptors or GPCRs. In 1988, a new era in the DAR field began with the cloning of the first receptor, the D2 receptor (D2R). Within the next few years, another four DARs were cloned and their structures elucidated.
Functions of Oncogene and Proto-Oncogene Protein Products
Published in Pimentel Enrique, Oncogenes, 2020
In general, the normal functions of p21c-ras proteins are little known but amino acids located at or near the carboxyl terminus of this proteins are required for lipid binding, membrane association and cellular transformation.84 Functional domains of p21ras molecules can be characterized by use of chimeric genes.85 Homology was detected between the human c-ras products and the beta subunit of mitochondrial and bacterial ATP-synthase86 Comparison of amino acid sequences revealed the presence of multiple homologous regions common to all members of the human c-ras family and the bacterial elongation factors Tu (EF-Tu) and G (EF-G), which also contain in their amino-terminal region a binding site for GTP.87 The alpha subunit of mammalian G proteins, which are guanine triphosphate (GTP)-binding proteins,88 which has structural homology with the middle portion of c-ras proteins, which suggests that both protein families (G proteins and c-ras proteins) may be derived from a common ancestor molecule. In the visual transducing system a G protein analogue, transducin, regulates GMP concentrations in the rod outer segment by inactivating a specific phosphodiesterase and a portion of the amino-terminal peptide sequence of transducin alpha subunit and bovine brain G protein shows homology to p21ras,89,90
Clinical Correlation between Acute Exudative Polymorphous Paraneoplastic Vitelliform Maculopathy and Metastatic Melanoma Disease Activity: A 48-month Longitudinal Case Report
Published in Ocular Immunology and Inflammation, 2022
Claire M Mueller, Sara L Hojjatie, David H Lawson, Nieraj Jain, Joshua Robinson, Mohammad K Khan, Melinda L Yushak, Ghazala A Datoo O’Keefe
Our patient had antiretinal antibodies to the photoreceptor proteins recoverin and transducin- α, and no demonstrable anti-bestrophin 1 antibodies.8 Recoverin is a calcium-binding phototransduction protein whose autoantibodies are associated with cancer-associated retinopathy, characterized by rapid and severe panretinal photoreceptor degeneration.17 Our patient did not demonstrate a typical retinal phenotype or disease course for anti-recoverin associated retinal degeneration. Transducin-α is a phototransduction-involved retinal G-protein whose autoantibodies can lead to retinal degeneration and have been previously reported in MAR.9,18,19 Anti-transducin associated AIR does typically follow a slower, milder course, as in our patient. However, we are not aware of any cases of AEPPVM associated with anti-transducin antibody, and it is unclear if this antibody played a role in the pathogenesis of this patient’s disease. Aside from testing for anti-bestrophin 1 antibodies, we did not perform an assay for other anti-RPE antibodies, therefore it is possible that this patient did have an unidentified anti-RPE antibody.
Novel homozygous in-frame deletion of GNAT1 gene causes golden appearance of fundus and reduced scotopic ERGs similar to that in Oguchi disease in Japanese family
Published in Ophthalmic Genetics, 2019
Daiki Kubota, Noriko Oishi, Kiyoko Gocho, Sachiko Kikuchi, Kunihiko Yamaki, Tsutomu Igarashi, Hiroshi Takahashi, Nobuo Ishida, Takeshi Iwata, Atsushi Mizota, Shuhei Kameya
The GNAT1 gene (OMIM *139330) encodes α subunit of rod transducin, a protein naturally expressed in vertebrate. Transducin is an important part of the phototransduction cascade (1,2) and is a trimeric G protein that consists of three subunits (3). The alpha-subunit binds to guanosine triphosphate (GTP) and activates cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE). The beta and gamma subunits form a complex that makes it possible for transducin to interact with rhodopsin (4). On exposure of the photoreceptor cells to light, rhodopsin is photoisomerized to its active form. This form activates transducin which then stimulates cGMP-PDE. The degradation of cGMP cause cGMP-gated ion channels to close resulting in hyperpolarization of the photoreceptors causing the electrical light response (5). The alpha-subunit is encoded by GNAT1 and is expressed in the rod cells, whereas the alpha-subunit that is encoded by GNAT2 is expressed in the cone cells (1,6).
Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options
Published in Ophthalmic Genetics, 2018
Nashila Hirji, Jonathan Aboshiha, Michalis Georgiou, James Bainbridge, Michel Michaelides
GNAT2 was the third gene found to be associated with ACHM, and accounts for less than 2% of all cases (42). GNAT2 mutations have been found in cases of both complete and incomplete ACHM (23,52). The variant c.461 + 24G>A which results in abnormal splicing in vitro is thought to result in an incomplete ACHM phenotype (52). Other mutations in this gene have been found to produce a truncated non-functional transducin protein (53). PDE6C mutations also account for less than 2% of ACHM cases, and in vitro studies have demonstrated that missense mutations result in enzymatic dysfunction, ranging from reduced to complete loss of activity (54). PDE6H mutations are the rarest cause of ACHM, accounting for less than 1% of affected individuals. The most recent gene, ATF6, accounts for 1–2% of ACHM with sequence variants found to cause both complete and incomplete ACHM (40).