Biology subjects

Yano, K.

Publications and source records attributed to Yano, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Data-driven frame-by-frame analysis of surface swimming and terrestrial walking in the coastal beetle Phaleria atriceps

Background. Inter-leg coordination of insects changes depending on environmental conditions. Although locomotor changes between terrestrial and aquatic environments have been examined in various insects, relatively little is known about coastal insects living at the boundary between these environments. We therefore compared the inter-leg coordination during terrestrial walking with that during surface swimming in the coastal beetle Phaleria atriceps. Methods. Surface swimming was recorded in 17 individuals and terrestrial walking in 10 individuals using high-speed video at 1,000 frames/s. The six leg tips and anterior and posterior body landmarks were tracked frame-by-frame using DeepLabCut, and leg movements were quantified in a body-centered coordinate system. Leg movement periods were estimated from sinusoidal fits to longitudinal leg-tip trajectories. Inter-leg phase relationships were calculated for all 15 leg pairs and integrated to reconstruct a representative six-leg phase organization for each locomotor mode. Results. Leg movement periods were significantly longer during surface swimming than during terrestrial walking for all six legs. During walking, the six-leg phase relationship closely matched an alternating tripod pattern, with a left foreleg (L1), a right middle leg (R2), and a left hind leg (L3) forming one phase group and a right foreleg (R1), a left middle leg (L2), and a right hind leg (R3) forming the opposing group. The same broad grouping was observed in the six-leg phase relationship during surface swimming, although significant differences in relative phase were detected for L1-L2, L1-R2, and R1-R2. Conclusions. Phaleria atriceps exhibited six-leg phase relationships broadly consistent with an alternating tripod pattern during both terrestrial walking and surface swimming, whereas leg movement periods and certain inter-leg phase relationships differed between the two locomotor modes. These findings provide a quantitative description of the similarities and differences in inter-leg coordination between terrestrial walking and surface swimming in a coastal beetle. Further mechanical and comparative studies will be needed to clarify the functional and evolutionary significance of these findings.

animal behavior and cognition↗

bioRxiv2026

Ile35 residue of SOD1 plays a key role in aggregate formation and eye degeneration in a Drosophila model of ALS

{middle dot}The pathophysiology of ALS caused by mutant SOD1 remains unclear. {middle dot}We previously demonstrated, using the BioID2-EGFP sandwich expression system in cultured cells, that the Ile35 residue of ALS-linked mutant SOD1 promotes its aggregate formation. {middle dot}However, the precise role of the SOD1 Ile35 residue in aggregate formation and neurodegeneration in vivo remained unclear. {middle dot}Drosophila expressing BioID2-G93A-EGFP demonstrated aggregate formation and eye degeneration with reduced eye size, whereas those expressing BioID2-G93A/I35S-EGFP showed less of these phenotypes. {middle dot}These findings highlight the crucial role of the Ile35 residue of ALS-linked SOD1 in aggregate formation and neurodegeneration in vivo.

neuroscience↗

bioRxiv2026

Detrimental effects of atomoxetine on visual signal detection in rats: Comparison with ADHD psychomotor stimulant drugs

RationaleAttention-deficit/hyperactivity disorder (ADHD) is associated with executive dysfunction involving inattention and impulsivity, with evidence of disrupted functional expression of the dopamine and noradrenaline transporters. ObjectiveWe investigated the dose-dependent modulation of anti-ADHD drugs on selective and sustained visual attention in low-, mid-and high-attention phenotypes. Two mathematical approaches, signal detection theory and theory of visual attention were applied to further characterise the effects and mechanisms. MethodsRats were trained to detect and respond to the presence or absence of a visual target to obtain food reward on a signal detection task. After attentional performance stabilised, the indirect catecholamine agonist, d-amphetamine (0.1; 0.2; 0.4 mg/kg), the dopamine (DA) and noradrenaline (NA) reuptake inhibitor methylphenidate (0.3; 1; 3 mg/kg), and the NA reuptake inhibitor atomoxetine (0.1; 0.3; 1 mg/kg), were administered systemically. ResultsLow-dose d-amphetamine produced baseline-dependent effects on attention, improving target discrimination only in rats with lower attentive performance, whereas methylphenidate did not significantly improve attention but increased guessing. In contrast, low-dose atomoxetine selectively impaired attention in low-attentive subjects, whereas high-dose atomoxetine generally impaired discrimination performance. All three drugs had expected effects on motor response output. ConclusionsAs well as demonstrating baseline-dependent effects of amphetamine on visual attention, the findings for methylphenidate and atomoxetine suggest important, apparently opposing effects on visual signal detection performance produced via blockade of the DA and NA transporters. The deleterious effects of atomoxetine on performance were especially noteworthy in view of its use as a treatment in ADHD.

animal behavior and cognition↗

bioRxiv2025

Reliable Detection of SGLT2 Protein through Knockout-based Antibody Characterization and Optimized Procedures

IntroductionSodium-glucose cotransporter 2 (SGLT2) is a key mediator of renal glucose reabsorption. Its pharmacological inhibition exerts cardio- and reno-protective benefits. Despite widespread clinical interest, reliable detection of SGLT2 protein remains challenging due to concerns regarding the specificity of available antibodies. MethodsThis study assessed the specificity of eight commercially available anti-SGLT2 antibodies by immunohistochemistry and Western blotting. Genetically engineered Sglt2-deficient mice and rats, generated via clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) technology, were employed as definitive negative controls. Additionally, human kidney tissues, including renal cell carcinoma samples, were analyzed. ResultsAmong the antibodies tested, few exhibited robust specificity, characterized by substantial immunostaining with minimal background in wild-type kidney tissues and complete absence of staining in Sglt2-deficient samples. In renal cell carcinoma samples, a validated antibody detected SGLT2 immunostaining in proximal tubules of non-tumor regions but not in tumor areas. Subcellular localization studies revealed that SGLT2 was enriched within proximal tubular microvilli, partially overlapping with its co-factor PDZK1IP1 (MAP17). LRP2 (megalin) and NHE3 were placed at the microvillar base and did not colocalize with SGLT2. Western blotting identified a specific SGLT2 band at approximately 55 kDa in kidney lysates using several antibodies under optimized procedures. This band was shifted to approximately 45 kDa after enzymatic removal of N-linked glycans. One antibody detected a weak band at the same molecular mass even in kidney lysates from Sglt2-deficient rodents. ConclusionsConsiderable variability exists in the specificity of commercially available anti-SGLT2 antibodies. Only a limited number of antibodies are suitable for reliable detection of SGLT2 in rodent and human samples. Rigorous antibody characterization, including the use of knockout controls and optimized experimental conditions, is essential to ensure reproducibility and prevent misinterpretation in studies investigating the biological and pathophysiological roles of SGLT2.

molecular biology↗

bioRxiv2025

Dopamine Dynamics in the Nucleus Accumbens Reflect Confidence in Detecting the Occurrence and Non-Occurrence of Visual Signals in Perceptual Decision-Making

Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision - making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced either by degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.

neuroscience↗

bioRxiv2023

Amino acid residues for specific binding to ssDNA facilitate topological loading of bacterial condensin MukB

The bacterial condensin MukB facilitates proper chromosome segregation in Escherichia coli. A portion of the MukB proteins localize at a specific chromosome region, binding to DNA in a non-sequence-specific manner. However, it is unclear how MukB localizes at a particular site without sequence specificity. Like other structural maintenance of chromosome (SMC) proteins, MukB topologically loads onto DNA, and It has an intrinsic property of preferential topological loading onto the single-stranded DNA (ssDNA). We consider it crucial for the localization of a specific region. To investigate the property of MukB, we attempted to identify positively charged amino acid residues responsible for ssDNA binding. We created a series of mutated MukB proteins in which a single positively charged amino acid was replaced with a negatively charged one. The results showed that some substitutions located on the inner surface of the MukB head domain impacted ssDNA-binding activity, leading to deficiencies in cell growth and nucleoid segregation. The efficiency of topological loading onto ssDNA was also decreased when the positive charges were replaced with negative ones. These amino acid residues align with and bind to ssDNA when the MukB dimer secures ssDNA within its ring, thereby likely strengthening the ssDNA-binding ability of MukB.

molecular biology↗

bioRxiv2023

Fruitless mating with the exes: the irreversible parthenogenesis in a stick insect

Parthenogenetic lineages, common in many animals, have sparked debate about their evolutionary persistence. While asexuality is expected to ensure reproductive assurance and provide a demographic advantage, parthenogens should suffer from the lack of gene shuffling with other individuals. On the other hand, occasional sexual reproduction has been theoretically predicted to be enough to mitigate the long-term costs of parthenogenesis. Recent studies have revealed instances of cryptic sex in some old parthenogenetic lineages, which is most likely mediated by rarely occurring males. Unlike female traits that rapidly become vestigial under asexuality, traits in males have been predicted to slowly decay due to the accumulation of neutral mutations over long evolutionary times. In fact, rare males often retain sexual functions, raising questions about the asexuality of these long-standing parthenogenetic lineages. Here, we intensively examined the possibility of sexual reproduction in the Japanese common stick insect, Ramulus mikado, which was also suggested to be an old parthenogen in our previous work. While asexual female reproduction appears to be quite predominant throughout Japan, we fortunately obtained the rare males from the field. These males exhibited typical stick insect male morphology and engaged in mating behaviors with conspecific females. However, no paternal-specific alleles were detected in the offspring; all embryos showed genotypes identical to their mothers. Our histological observations on a few males revealed that they had no sperm in their reproductive organs, although the degree of decay may be different among the lineages. We also found that females have sexual organs with signs of degeneration. All these results demonstrate the irreversible asexual reproduction of R. mikado and indicate their long history as a parthenogenetic species. Our present study provides unique insights into the maintenance of parthenogenesis and degenerative evolution of sexual traits in ancient asexual lineages.

evolutionary biology↗

bioRxiv2023

Definitive environmental DNA research on aquatic insects: Analysis optimization using the recently developed MtInsects-16S primers set

Long-term biodiversity monitoring is necessary for the conservation and management of water resources. Notably, aquatic insects have been used as an indicator of water quality because they provide important basic information about freshwater ecosystems and water resources. Although environmental DNA (eDNA) surveys can enable easy and effective biomonitoring of aquatic insects, previous studies have not successfully detected all insect species, and there has been frequent amplification of nontarget taxa (e.g., algae and diatoms). Therefore, we developed a universal primers set, MtInsects-16S, for eDNA analyses of insects in the mtDNA 16SrRNA region. Furthermore, a well-established database of aquatic insects, especially the MtInsects-16S DNA region of Ephemeroptera, Plecoptera, and Trichoptera in Kanagawa Prefecture, which was the target area in this study, was constructed. Therefore, in this study, we conducted eDNA analyses using a universal primers set and using a well-established database. We conducted and compared capture surveys at the same sites to examine the detection capability of eDNA for Insecta. As a result, eDNA analyses using MtInsects- 16S not only detected almost all of the captured species but also detected many more species without amplifying nontarget taxa. This study demonstrated the application of eDNA analyses with unprecedented accuracy and reliability. It was also shown that community structure by eDNA reflected a relatively narrow range at the water sampling point. Although the data accumulation for constructing locally specific databases is an urgent issue, using the MtInsects-16S region is expected to be a breakthrough in the metabarcoding of insects.

zoology↗

bioRxiv2023

Autonomous development and regeneration of isolated rice egg cells in a fertilization-independent manner

Parthenogenesis is suppressed in rice egg cells to avoid precocious development before fertilization. We found that cold treatment released cell cycle arrest in egg cells and triggered mitosis. Egg cells isolated from japonica (Nipponbare; NB) and aus (Kasalath; KS) subspecies divided and regenerated into mature plants after cold treatment. The egg-derived plants showed variety of ploidy levels, including haploid (n), diploid (2n), and tetraploid (4n). Nuclear DNA quantification showed that genome duplication occurred during early parthenogenetic development. Owing to the presence of single nucleotide polymorphisms (SNPs) between NB and KS, inter-subspecific hybrid plants (NB-KS hybrids) were created via electrofusion. Egg cells from the NB-KS hybrid developed parthenogenetically into polyploid plants. 2n and 4n plants originating from the same NB-KS egg cell displayed the same homozygous SNP patterns throughout the genome, indicating that these plants were doubled and quadrupled haploids. Transcriptome analyses of cold-treated egg cells demonstrated that parthenogenesis-related candidate genes, including OsBBML1, were upregulated.

plant biology↗

bioRxiv2022

Phylogeography of Geothelphusa freshwater crabs: unexpected dual dispersal routes via land and sea

AimDispersal is an important factor that determines the potential for colonization to pioneer sites. Most decapods employ seaward migration for reproduction with a planktonic larval phase. However, true freshwater crabs spend their entire life cycle in freshwater. Therefore, it is expected that genetic regionality can be easily detected. In this study, we focused on the genetic structures of true freshwater crabs, Geothelphusa crabs. Herein, we reveal the evolutionary history and dispersal patterns of freshwater crustaceans, for which there is limited knowledge to date. LocationJapanese Islands TaxonGeothelphusa dehaani (Decapoda, Potamidae) MethodsWe collected and genetically analyzed 283 specimens at 138 localities from freshwater habitats across the Japanese Islands. Phylogenetic analyses were conducted on 1,796 bp of the combined dataset (mtDNA COI, 16S, and nDNA ITS1, histone H3) and 569 bp of the mtDNA COI dataset. The demographic history of G. dehaani was simulated using Approximate Bayesian Computation analysis. A salt tolerance experiment was conducted to confirm the survival rate in seawater. ResultsThe resulting of phylogenetic relationships detected 10 clades that were highly likely to be monophyletic. These 10 clades genetically exhibited an explicit pattern of geographical differentiation. Also, we confirmed the salt tolerance ability of these Japanese freshwater crabs. Main conclusionsThe highlights of this study were the discovery of several cryptic species/lineages or undescribed species, and the completely different heterogeneous dual dispersal pathways detected within a single species; i.e., both land and ocean routes. As a result of phylogenetic analysis, it was concluded that Japanese crabs are basically genetically divided by straits. However, strong evidence for dispersion via ocean currents was also detected (i.e., a "sweepstake"), and it was also determined that G. dehaani could survive in seawater. This is the first observation of such a unique mode of expansion of a species distribution area.

zoology↗

bioRxiv2021

Development of novel PCR primer sets for DNA metabarcoding of aquatic insects, and the discovery of some cryptic species

DNA barcoding is a powerful tool that provides rapid, accurate, and automatable species identification by using standardized genetic region(s). It can be a powerful tool in various fields of biology such as for revealing the existence of cryptic species and/or rare species and in environmental science such as when monitoring river biota. Biodiversity reduction in recent times has become one of the most serious environmental issues on a worldwide scale. DNA barcoding techniques require the development of sets of universal PCR primers for DNA metabarcoding. We tried to develop universal primer sets for the DNA barcoding of all insect groups. In this study, we succeeded in designing not only universal primer sets for DNA barcoding regions of almost all insects, which were designed to include a hypervariable site between highly conserved sites, but also primer sets for longer fragment sequences for registration in a database. We confirmed successful amplification for 14 orders, 43 families, and 68 species with DNA barcoding in the mtDNA 16S rRNA region, and for 13 orders, 42 families, and 66 species with DNA barcoding in the mtDNA 12S rRNA region. A key feature is that the DNA fragments of the DNA barcoding regions amplified by these primer sets are both short at about 200-bp, and longer fragment sequences will increase the level of data registration in the DNA database. Such resulting database enhancements will serve as a powerful tool for increasingly accurate assessment of biodiversity and genetic diversity.

ecology↗

bioRxiv2021

Dominant Awn Inhibitor, which encodes an ALOG protein in sorghum, suppresses awn formation in rice

The awn, a needle-like structure extending from the tip of the lemma in grass species, plays a role in environmental adaptation and fitness. In some crops, awns appear to have been eliminated during domestication. Although numerous genes involved in awn development have been identified, several dominant genes that eliminate awns are also known to exist. For example, in sorghum (Sorghum bicolor), the dominant awn inhibiting gene has been known since 1921; however, its molecular features remain uncharacterized. In this study, we conducted quantitative trait locus analysis and a genome-wide association study of awn-related traits in sorghum and identified DOMINANT AWN INHIBITOR (DAI), which encodes the ALOG family protein on chromosome 3. DAI appeared to be present in most awnless sorghum cultivars, likely because of its effectiveness. Detailed analysis of the ALOG protein family in cereals revealed that DAI originated from duplication of its twin paralog (DAIori) on chromosome 10. Observations of immature awns in near-isogenic lines revealed that DAI inhibits awn elongation by suppressing both cell proliferation and elongation. We also found that only DAI gained a novel function to inhibit awn elongation through an awn-specific expression pattern distinct from that of DAIori. Interestingly, heterologous expression of DAI with its own promoter in rice inhibited awn elongation in the awned cultivar Kasalath. We found that DAI originated from gene duplication, providing an interesting example of gain-of-function that occurs only in sorghum but shares its functionality with rice and sorghum.

plant biology↗

bioRxiv2021

Temporal Changes in Transcripts of MITE Transposable Elements during Rice Endosperm Development

The repression of transcription from transposable elements (TEs) by DNA methylation is necessary to maintain genome integrity and prevent harmful mutations. However, under certain circumstances, TEs are thought to escape from the host defense system and reactivate their transcription. In Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), DNA demethylases target the sequences derived from TEs in the central cell, the progenitor cell for the endosperm in the female gametophyte. This genome-wide DNA demethylation is also observed in the endosperm after fertilization. In this study, we used a custom microarray to survey the transcripts generated from TEs during the rice endosperm development and at selected timepoints in the embryo as a control. The expression patterns of TE transcripts are dynamically up- and downregulated during endosperm development, especially for miniature inverted-repeat transposable elements (MITEs). Surprisingly, some TE transcripts were directionally controlled, while the other DNA transposons and retrotransposons were not. We also discovered the NF-Y binding motif, CCAAT, in the region near the 5' terminal inverted repeat of Youren, one of the transcribed MITEs in the endosperm. Our results uncover dynamic changes in TE activity during endosperm development in rice.

plant biology↗

bioRxiv2021

Identification of a divergent basal body assembly protein involved in land plant spermatogenesis

Oogamy is a form of sexual reproduction and evolved independently in animals, fungi, and plants. In streptophyte plants, Charophyceae, Coleochaetophyceae, bryophytes, lycophytes, ferns (monilophytes), and some gymnosperms (Cycads and Ginkgo) utilize spermatozoids as the male gamete. Plant spermatozoids commonly possess characteristic structures such as the spline, which consists of a microtubule array, the multilayered structure (MLS) in which the uppermost layer is continuum of the spline, and multiple flagella. However, the molecular mechanisms underpinning plant spermatogenesis remain to be elucidated. To identify the genes involved in plant spermatogenesis, we performed computational analyses and successfully found deeply divergent BLD10s by combining multiple methods and omics-data. We then validated the functions of candidate genes in the liverwort Marchantia polymorpha and the moss Physcomitrium patens and found that MpBLD10 and PpBLD10 are required for normal basal body and flagella formation. Mpbld10 mutants exhibited defects in remodeling of the cytoplasm and nucleus during spermatozoid formation, thus MpBLD10 should be involved in chromatin reorganization and elimination of the cytoplasm during spermiogenesis. Streptophyte BLD10s are orthologous to BLD10/CEP135 family proteins, which function in basal body assembly, but we found that BLD10s evolved especially fast in land plants and MpBLD10 might obtain additional functions in spermatozoid formation through the fast molecular evolution. This study provides a successful example of combinatorial study from evolutionary and molecular genetic perspectives that elucidated a function of the key protein of the basal body formation that fast evolved in land plants.

evolutionary biology↗

bioRxiv2021

Profiling a single-stranded DNA region within an rDNA segment that is a loading site for bacterial condensin

Bacterial condensin preferentially loads to single-stranded DNA (ssDNA) in vitro and loads onto rDNA in vivo to support proper chromosome compaction. Thus, the actively transcribing rDNA would provide the ssDNA region for the topological loading of bacterial condensin. We attempted to detect the ssDNA region in the rrnI gene in situ. Non-denaturing sodium bisulfite treatment catalyzed the conversion of cytosines to thymines via uracils (CT-conversion) at locally melted DNA of a bacterial genome. Using next-generation sequencing, we generated an average of 11,000 reads covering each cytosine on the PCR-amplified rDNA segment to obtain the actual CT-conversion rate. In principle, the CT-conversion rate is an accurate guide to detect the formation of the ssDNA segment. We expected that an increment of the CT-conversion rate would reflect a trend toward ssDNA accumulation at a given site within the rDNA. We detected multiple ssDNA segments throughout the rDNA. The deletion mutations of the rDNA that affect the bacterial-condensin loading hindered the ssDNA formation only at the 100-500 bp segment downstream of the promoter. These data support the idea that the ssDNA segment plays a crucial role as the bacterial condensin-loading site and suggest the mechanism of condensin loading onto rDNA.

molecular biology↗

bioRxiv2020

Asymbiotic mass production of the arbuscular mycorrhizal fungus Rhizophagus clarus

Arbuscular mycorrhizal (AM) symbiosis is a mutually beneficial interaction between fungi and land plants and promotes global phosphate cycling in terrestrial ecosystems. AM fungi are recognised as obligate symbionts that require root colonisation to complete a life cycle involving the production of propagules, asexual spores. Recently it has been shown that Rhizophagus irregularis can produce infection-competent secondary spores asymbiotically by adding a fatty acid, palmitoleic acid. Further, asymbiotic growth can be supported using myristate as a carbon and energy source for their asymbiotic growth to increase fungal biomass. However, spore production and the ability of these spores to colonise host roots were still limited compared to co-culture of the fungus with plant roots. Here we show that a combination of two plant hormones, strigolactone and methyl jasmonate, induces production of a large number of infection-competent spores in asymbiotic cultures of Rhizophagus clarus HR1 in the presence of myristate and organic nitrogen. Inoculation of asymbiotically-generated spores promoted the growth of Welsh onions, as observed for spores produced by symbiotic culture system. Our findings provide a foundation for elucidation of hormonal control of the fungal life cycle and development of new inoculum production schemes.

microbiology↗

bioRxiv2020

Development of microsatellite markers for a giant water bug, Appasus japonicus, distributed in East Asia

We developed microsatellite markers for Appasus japonicus (Hemiptera: Belostomatidae). This belostomatid bug is distributed in East Asia (Japanese Archipelago, Korean Peninsula, and Mainland China), and often listed as endangered species in the Red List or the Red Data Book at the national and local level in Japan. Here we describe twenty novel polymorphic microsatellite loci developed for A. japonicus, and marker suitability was evaluated on 56 individuals from four A. japonicus populations (Nagano, Hiroshima, and Yamaguchi prefecture, Japan, and Chungcheongnam-do, Korea). The number of alleles per locus ranged 1-12 (mean = 2.5), and average observed and expected heterozygosity, and fixation index per locus were 0.270, 0.323, and 0.153, respectively. The 20 markers described here will be useful for investigating the genetic structure of A. japonicus populations, which can contribute in population genetics studies of this species.

molecular biology↗

bioRxiv2020

Gastrointestinal absorption of pimozide is enhanced by inhibition of P-glycoprotein

Following the death due to cardiac arrest of a patient taking pimozide, sertraline and aripiprazole antipsychotic/antidepressant combination therapy, a role of drug-drug interaction was suggested. Here, we investigated P-glycoprotein (P-gp)-mediated interaction among the three drugs using in vitro methods. Sertraline or aripiprazole significantly increased the permeability of pimozide in Caco-2 cell monolayers. ATPase assay indicated that pimozide is a P-gp substrate, and might act as a P-gp inhibitor at higher concentrations. The values of the kinetic parameters of carrier-mediated efflux, calculated from the concentration dependence of pimozide efflux from LLC-GA5-COL150 cells expressing human P-gp, were as follows: maximum transport rate (Jmax) = 84.9 {+/-} 8.9 pmol/min/mg protein, half-saturation concentration (Kt) = 10.6 {+/-} 4.7 M, first-order rate constant (kd) = 0.67 {+/-} 0.14 pmol/min/mg protein. Further, the efflux ratio of pimozide in LLC-GA5-COL150 cells was significantly decreased in the presence of sertraline or aripiprazole. These results indicate that pimozide is a substrate of P-gp, and its efflux is inhibited by sertraline and aripiprazole. Thus, P-gp inhibition by sertraline and/or aripiprazole may alter the gastrointestinal permeability of co-administered pimozide, resulting in an increased blood concentration of pimozide, which may increase the likelihood of pimozides known life-threatening side effect of QT prolongation.

pharmacology and toxicology↗