MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus

Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0 MB to 43.8 MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia, severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder.     

Pharmacological profiles of aminoindanes,piperazines, and pipradrol derivatives

Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in “Ecstasy” tablets as replacements for 3,4-methylenedioxymethamphetamine (MDMA) or substances sold as “ivory wave.” The pharmacology of these MDMA- and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the pipradrol derivatives desoxypipradrol (2-diphenylmethylpiperidine [2-DPMP]), diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]), and methylphenidate. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine [5-HT]) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporters (NET, DAT, and SERT). We also evaluated the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells and the binding affinity to monoamine transporters and receptors, including trace amine-associated receptor 1 (TAAR₁). 5-IAI and MDAI preferentially inhibited the SERT and NET and released 5-HT. 2-AI interacted with the NET. BZP blocked the NET and released DA. m-CPP and TFMPP interacted with the SERT and serotonergic receptors. The pipradrol derivatives were potent and selective catecholamine transporter blockers without substrate releasing properties. BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR₁ binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability.     

The protein Ocular albinism 1 is the orphan GPCR GPR143 and mediates depressor and bradycardic responses to DOPA in the nucleus tractus solitarii

Background and Purpose: L-DOPA is generally considered to alleviate the symptoms of Parkinson''s disease by its conversion to dopamine. We have proposed that DOPA is itself a neurotransmitter in the CNS. However, specific receptors for DOPA have not been identified. Recently, the gene product of ocular albinism 1 (OA1) was found to exhibit DOPA-binding activity. Here, we have investigated whether OA1 is a functional receptor of DOPA in the nucleus tractus solitarii (NTS).Experimental Approach: We examined immunohistochemical expression of OA1 in the NTS, and the effects of DOPA microinjected into the depressor sites of NTS on blood pressure and heart rate in anaesthetized rats, with or without prior knock-down of OA1 in the NTS, using shRNA against OA1.Key Results: Using a specific OA1 antibody, OA1-positive cells and nerve fibres were found in the depressor sites of the NTS. OA1 expression in the NTS was markedly suppressed by microinjection into the NTS of adenovirus vectors carrying the relevant shRNA sequences against OA1. In animals treated with OA1 shRNA, depressor and bradycardic responses to DOPA, but not those to glutamate, microinjected into the NTS were blocked. Bilateral injections into the NTS of DOPA cyclohexyl ester, a competitive antagonist against OA1, suppressed phenylephrine-induced bradycardic responses without affecting blood pressure responses.Conclusion and Implications: OA1 acted as a functional receptor for DOPA in the NTS, mediating depressor and bradycardic responses. Our results add to the evidence for a central neurotransmitter role for DOPA, without conversion to dopamine.     

抗抑郁药的研究新进展

抑郁症正成为一个严重的全球问题。目前抗抑郁药物分四大类：单胺氧化酶抑制剂（Monoamine oxidase inhibitors,MAOIs）、三环类药物（Tricyclicantide pressants,TCAs）、选择性5-色胺再摄取抑制剂（Selective serotonin reuptake inhibitors,SSRIs）、新型抗抑郁药。     

Nonselective cation permeation in an AMPA-type glutamate receptor

Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a nonselective cation channel, which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamic (MD) simulations on a putative open-state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na⁺, K⁺, and Cs⁺ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na⁺ and K⁺ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a water-filled cavity with a cone shape that lacked major interactions with ions. We observed that Cl⁻ readily enters the upper pore, explaining anion permeation in the RNA-edited (Q586R) form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, nonselective cation permeation and copermeation by water. Simulations suggested Cs⁺ uses two equally populated ion binding sites in the filter, and we confirmed with electrophysiology of GluA2 that Cs⁺ is slightly more permeant than Na⁺, consistent with serial binding sites preferentially driving selectivity.

Glutamate receptor ion channels are found at synapses throughout the vertebrate nervous system, where they convert submillisecond glutamate signals into cation currents. Advances in structural biology have provided molecular scale maps of their ion pores, permitting comparison with a burgeoning menagerie of structures from related ion channels. It has been comparatively difficult to obtain candidate open pore structures of glutamate receptors, with the notable exceptions being from single-particle cryo-electron microscopy (Cryo-EM) of complexes between GluA2 and Stargazin (1, 2), the prototypical transmembrane AMPA receptor regulatory protein (TARP). However, it is unclear from simple inspection of these structures whether 1) the ion pore is conductive or 2) it is open to its fullest extent or to the highest conductance level. One structure has the unedited form of GluA2 (Q), that is, GluA2 lacking the common RNA editing of the Q586 residue to Arginine (3), while the other structure is of the edited form (Q586R), which should have a low conductance (4). Previous electrophysiological work suggests that the radius of the narrowest part of the AMPA channel [either with or without Stargazin (5, 6)] is 4 Å, and neither the upper gate nor the selectivity filter (SF) are this wide in either candidate open structure. However, these estimates are based on the geometric mean radius of large, elongated cations. A substantial body of electrophysiological work provides good benchmarks for how permeation should proceed in an open AMPA receptor pore. For example, canonical measurements of reversal potentials show that alkali earth cations from sodium (Na⁺) up to cesium (Cs⁺) should permeate GluA1 (7) and GluA2 (Q) (8) approximately equally well and that the single channel conductance of the full level of GluA2 (Q) should be considerable [∼30 pS (9)].Most computational work on ion permeation through channels has been focused on simple, selective potassium (K⁺) channels like KcsA (10–12), being the first reported crystal structures of ion channels (13). Thanks to their minimal sequences, these channels demand little computational overhead. Their key structural features are two membrane-spanning helices and a reentrant loop forming a narrow SF for permeant ions. This core motif defines a superfamily of tetrameric and pseudotetrameric channels that encompass selective, semiselective, and nonselective cation conductances. In common with many eukaryotic channels, the AMPA-type glutamate receptor (AMPAR) has a pore domain whose gating state is controlled by substantially larger domains outside the membrane (amino terminal domain [ATD] and ligand-binding domain [LBD], Fig. 1A), which account for about 75% of the protein mass. The large size presents a challenge for conventional molecular dynamic (MD) simulations, with the AMPA receptor being about six-times bigger than KcsA.Open in a separate windowFig. 1.AMPA receptor and the simulation setup. (A) The activated open state of the AMPA receptor from Cryo-EM [PDB ID: 5WEO (1)] with Stargazin molecules removed. The receptor is composed of ATD, LBD, and TMD. (B) The TMD and linkers to the LBD layer were included the MD simulations. The sites where the linkers were truncated and physically restrained (see Methods) are marked with red balls. Two out of the four subunits are shown. (C) The SF region of the AMPA receptor pore, with key residues labeled. Again, only two diagonally opposed subunits are drawn. (D) The computational electrophysiology setup was composed of two tetrameric AMPA channels, each embedded in a separate POPC lipid bilayer, solvated with water molecules and ions. A small cation imbalance between the two compartments α and β was maintained during the simulations. The resulting gradient gave a transmembrane potential to drive ion permeation.It remains to be seen to what extent key features of ion permeation elucidated in prokaryotic channels (selectivity, discrete sites, desolvated ions, and block by divalent ions) are widely applicable in channels with more substantial architectures. Recent experimental and MD work on nonselective prokaryotic channels like NaK and NaK-CNG as well as a mutant of the human hERG1 channel suggests that ion permeation in these channels differs substantially from classical K⁺-selective ion permeation (14–17). The SF of nonselective cation channels is much more flexible, with fewer ion binding sites leading to distinct conduction mechanisms and hydration states for Na⁺ and K⁺ when passing through the filter. In the AMPA receptor, in one activated open Cryo-EM structure of GluA2 (1), density for a presumptive hydrated sodium ion was observed adjacent to the unedited Q586 residue. In the structure of RNA-edited GluA2 (Q586R) with Stargazin (2), ions were absent. The closed state structure of a GluA1/A2 heteromer featured strong density of unknown identity adjacent to C589 (18). Whether the paucity and heterogeneity of resolved ions is due to a lack of order in the filter region, the lack of detail in the coulomb potential density, or a true deficit of ions remains unclear. However, observations in these AMPA receptor structures are in marked contrast to the Cryo-EM structures of several other nonselective cation channels, such as hyperpolarization-activated cyclic nucleotide-gated (HCN) (19) and cyclic nucleotide-gated (CNG) channels (20), where two or three bound ions were visible. Further context comes from canonical K⁺-selective channels, which feature up to four ions in a row (21), and crystal structures of Ca²⁺-selective transient receptor potential (TRP) channels where two Ca²⁺ ions were readily resolved (22).Here, we used MD-based computational electrophysiology to examine ion permeation through the mammalian AMPA receptor ion channel. We determined that the published structure is stably open, suitably detailed for MD simulations, and most likely represents a native fully open state. We identified a minimal SF consisting of a single major ion binding site that does not fully dehydrate ions. In simulations, Cs⁺ co-opted a secondary binding site. Consistent with multiple sites promoting ion selectivity, electrophysiology of AMPARs in human embryonic kidney (HEK293) cells showed that Cs⁺ is slightly more permeant than Na⁺.     

Biological Activities of 2-Mercaptobenzothiazole Derivatives: A Review

2-Mercaptobenzothiazoles are an important class of bioactive and industrially important organic compounds. These compounds are reported for their antimicrobial and antifungal activities, and are subsequently highlighted as a potent mechanism-based inhibitor of several enzymes like acyl coenzyme A cholesterol acyltransferase, monoamine oxidase, heat shock protein 90, cathepsin D, and c-Jun N-terminal kinases. These derivatives are also known to possess antitubercular, anti-inflammatory, antitumor, amoebic, antiparkinsonian, anthelmintic, antihypertensive, antihyperlipidemic, antiulcer, chemoprotective, and selective CCR3 receptor antagonist activity. This present review article focuses on the pharmacological profile of 2-mercaptobenzothiazoles with their potential activities.