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Pharmacotherapy of Neurochemical Imbalances
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar, Suvarna Ingale
cAMP is a low-molecular-weight, hydrophilic second messenger formed by ATP hydrolysis by a membrane bound enzyme AC which is coupled with G-proteins. As AC is activated, there is rise in intracellular cAMP leading to stimulation of a number of proteins, for example, cAMP can modulate the opening of some cationic channels that possess a binding domain for cyclic nucleotide binding domain (CNBD). cAMP also activates the protein kinase A (PKA) (Greengard and Kebabian, 1974).
Variable expressivity in patients with autosomal recessive retinitis pigmentosa associated with the gene CNGB1
Published in Ophthalmic Genetics, 2021
Bojana Radojevic, Kaylie Jones, Martin Klein, Margarita Mauro-Herrera, Ronald Kingsley, David G. Birch, Lea D. Bennett
The missense variant c.2957A>T, p.Asn986Ile is located in the cyclic nucleotide-binding domain (CNBD) which impairs cGMP binding resulting in a non-functional channel (14,38). The other 2 missense variants found in our patients, c.2127 C > G, p.Phe709Leu and c.2092 T > C, p. Cys698Arg, alter highly conserved amino acid residues within transmembrane domains (TM) close to TM1 (Figure 2). A recent study detected a strong physical interaction between an N-terminal region of CNGB1 (amino acids 677–764) and a C-terminal region of CNGA1. The results imply that a CNGA1/CNGB1 inter-subunit interaction regulates membrane expression which is required for surface targeting of intact channels (39). Therefore, pathogenic variants in this region possibly prevent CNG channels from localizing to the surface of rod cells, resulting in abnormal outer segment development, metabolic overload, dysfunction of retinal pigment epithelial cells, and sustained activation of the photoreceptor (40).
Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure
Published in Journal of Receptors and Signal Transduction, 2018
G-protein coupled receptor components of cell membrane and G-alpha proteins provide receptors compatible, to some degree, with purine nucleotide structure. Ligand binding to the former structure releases nucleotide from the latter as part of the signal transduction process. The concept of interaction between cell membrane receptor-bound ligand and cytosol protein-bound nucleotide is made more feasible in the light of recent structural analysis and modeling of cell signal transduction processes. Chung and coworkers, using peptide-amide hydrogen-deuterium exchange mass spectrometry, describe post-activation movement of the carboxyl terminus of GDP-bound Gαs as a rigid-body translation upwards into the receptor core to reorganize the loop forming part of the nucleotide pocket [45]. Subsequent reorganization of the β1 strand leads to loss of co-ordination of the β-phosphate of GDP, release of GDP and formation of the nucleotide-free form. Kowal et al. [46] describe a model coupling ligand-gating and voltage-sensing in the cyclic nucleotide-modulated potassium channel MloK1, whereby activation allows the cyclic nucleotide-binding domain to move vertically towards the membrane, permitting direct contact with voltage sensor domains.
Exome sequencing identification of susceptibility genes in Chinese patients with keratoconus
Published in Ophthalmic Genetics, 2020
Liyan Xu, Kaili Yang, Qi Fan, Yuwei Gu, Bo Zhang, Chenjiu Pang, Shengwei Ren
Among all the susceptibility genes, TRANK1 is found on chromosome 3 and encodes tetratricopeptide repeat and ankyrin repeat containing 1. The protein presents significant expression in brain and has been associated with DNA/ATP binding or DNA repair (27). Previous study indicated the decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation (28). Thus, the variant (c.1168 T > C) in THANK1 might affect KC via influencing ocular development. ERMP1, located on 9p24, is a zinc-binding protease belonging to the peptidase M28 family, with nine predicted transmembrane domains normally localized in endoplasmic reticulum (29). Grandi et al. (29) found ERMP1 might play roles in the defense against oxidative stress. Studies have identified oxidative stress is implicated in the pathogenesis of KC (30,31). Then, we inferred the c.341A>T in ERMP1 might correlate with the disease. SDK2, located on 17q25, encodes a protein belong to immunoglobulin superfamily. It has been shown that SDK2 can promote lamina-specific connectivity in the development of retina (32). And it is important for the formation of the retinal circuit that detects differential motions (33). However, association studies between SDK2 and KC haven’t been reported. The relationship between SDK2 and KC still need to be further explored. There were also two collagen related genes, COL6A1 in chromosome 21 and COL9A3 in chromosome 20, identified as susceptibility genes for KC. COL6A1 encodes a constituent chain of type VI collagen, which is present in human corneal stroma (34). A recent genome wide association study found COL6A1 was associated with corneal biomechanical properties in KC, indicating a suggestive association with the disease (35). Similarly, COL9A3 encodes one of the three alpha chains of type IX collagen, which is also present in human cornea (36). But there existed no studies suggesting an associated between COL9A3 and ocular diseases to date. CNBD1 is cyclic nucleotide binding domain containing 1. And the CNBD1 had previously been implicated in the subcellular targeting of EPAC2A (catalytic domains of the cAMP sensors), playing important roles in cAMP signaling (37). In the present study, we found a stop gain mutation in CNBD1 might be relevant to KC. The dysfunction of CNBD1 might result in abnormal cAMP signaling, subsequently influencing the occurrence of the disease. KRT82 is a member of the keratin gene family. Variant in KRT82 has been identified as hotspot mutation in sporadic microsatellite-instable colorectal cancers (38). Studies have identified a correlation between other keratin gene and KC (39,40), but there existed no reports indicating a relationship of KRT82 with ocular diseases. NSUN5 is a cytosine-5 RNA methyltransferase which was selectively expressed in radial glial cells during embryonic cortex (41). The deletion of NSUN5 has been reported in about 95% patients with Williams–Beuren syndrome (41). And there have been reported several cases indicating an association between KC and Williams–Beuren syndrome (42–44). Therefore, we speculated there might be a potential role for NSUN5 in the pathogenesis of KC.