Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping

In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABA A receptor subunits, often referred to as synaptic GABA A (gamma subunit) and extra-synaptic GABA A (delta subunit). To test the functional roles of these distinct GABA A in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABA A receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABA A reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABA A densities could enhance synchrony, as opposed to increasing delta GABA A densities. Overall, our model reveals how blocking GABA A receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABA A density in the winter could underlie the tighter phase relationships among SCN cells.

Association study of genetic polymorphisms in GABRD with treatment response and dose in methadone maintenance treatment

Aim: This study determined if gene variants in the GABA receptor delta subunit ( GABRD) are associated with treatment response and dose in methadone maintenance treatment (MMT) for heroin addiction. Materials & methods: A total of 286 MMT patients were recruited and divided into response and nonresponse groups based on retention time in therapy. A total of 177 responders were classified into low dose and high dose subgroups according to the stabilized methadone dose. Four (single nucleotide polymorphisms) SNPs (rs13303344, rs4481796, rs2376805 and rs2229110) in GABRD were genotyped using the TaqMan SNP assay. Logistic regression was used to assess the genetic effects of the SNPs in MMT. Results: No significant associations were observed between the SNPs and treatment response or dose, except the frequency of haplotype ACGC at the four SNPs significantly differed between responders and nonresponders. Conclusion: The results indicated that GABRD variants may play a small role in modulating methadone treatment response.

Gabapentin-induced bilateral lower extremity edema in a patient with pervasive developmental disorder and schizoaffective disorder

Gabapentin binds to the alpha-2-delta subunit of presynaptic voltage-gated calcium channels and is used for a wide variety of on- and off-label indications. Gabapentin is dosed at total daily doses ranging from 300 to 3600 mg/d, which is generally divided into 3 doses. Although gabapentin is generally well tolerated, 1 potential reported adverse effect is peripheral edema. However, due to the extensive number of etiologies of peripheral edema, medication causes may be overlooked on an inpatient psychiatric unit. This is a case of delayed identification of a probable adverse drug reaction to gabapentin (Naranjo score of 5) consisting of painful, 4+ pitting bilateral edema and a clear dose relationship in a patient with pervasive developmental disorder and schizoaffective disorder.

Plasmodiumchaperonin TRiC/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy

The antihistamine clemastine inhibits multiple stages of thePlasmodiumparasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to thePlasmodium falciparumTCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eightP. falciparumTRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a clemastine-induced thermodynamic stabilization of thePlasmodiumTRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that clemastine reduces levels of the major TRiC substrate tubulin inP. falciparumparasites. In addition, clemastine treatment leads to disorientation ofPlasmodiummitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively targetPlasmodiumTRiC-mediated protein folding for malaria intervention.