Transporter-encoding Genes Research Articles

Negative regulation of Candida glabrata Pdr1 by the deubiquitinase subunit Bre5 occurs in a ubiquitin independent manner

The primary route for development of azole resistance in the fungal pathogen Candida glabrata is acquisition of a point mutation in the PDR1 gene. This locus encodes a transcription factor that upon mutation drives high level expression of a range of genes including the ATP-binding cassette transporter-encoding gene CDR1. Pdr1 activity is also elevated in cells that lack the mitochondrial genome (ρ° cells), with associated high expression of CDR1 driving azole resistance. To gain insight into the mechanisms controlling activity of Pdr1, we expressed a tandem affinity purification (TAP)-tagged form of Pdr1 in both wild-type (ρ+ ) and ρ° cells. Purified proteins were analyzed by multidimensional protein identification technology mass spectrometry identifying a protein called Bre5 as a factor that co-purified with TAP-Pdr1. In Saccharomyces cerevisiae, Bre5 is part of a deubiquitinase complex formed by association with the ubiquitin-specific protease Ubp3. Genetic analyses in C. glabrata revealed that loss of BRE5, but not UBP3, led to an increase in expression of PDR1 and CDR1 at the transcriptional level. These studies support the view that Bre5 acts as a negative regulator of Pdr1 transcriptional activity and behaves as a C. glabrata-specific modulator of azole resistance.

Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate are not transported by Concentrative Nucleoside Transporter 2

Tenofovir-associated renal toxicity is influenced by several factors, including plasma exposure and genetic variants in transporter-encoding genes. Tenofovir plasma exposure has been associated with a polymorphism in SLC28A2 gene (encoding the concentrative nucleoside transporter 2, CNT2): particularly, SLC28A2 124 CT/TT genotype patients show higher plasma tenofovir concentrations, compared to CC group.In literature, substrate studies are lacking; for this reason, our aim was to understand if tenofovir and tenofovir-alafenamide are CNT2 substrates.We performed an in vitro study using CNT2 expressing MDCKII cells.We observed that tenofovir and tenofovir-alafenamide are not substrates of CNT2.Tenofovir-alafenamide influx pathway remains to be clarified.

Apigenin pretreatment enhances growth and salinity tolerance of rice seedlings

Soil salinity is a limiting factor in rice production. Since flavonoids present in most plant tissues play multiple roles in plant-environment interactions, in this study, we focused on the contribution of flavone aglycone (Apigenin) to the adaptation of salinity-sensitive rice cultivar ‘Koshihikari,’ to salinity stress, for the first time. Rice seeds were soaked in Apigenin solution (10 ppm) for 24 h, then air-dried and grown hydroponically under 50 mM NaCl for 14 days. Apigenin pretreatment improved the growth of rice seedlings by enhancing shoot elongation and dry mass accumulation under both unstressed and NaCl-stress conditions, compared with that in the non-pretreated seedlings. Apigenin pretreatment significantly reduced Na+ accumulation in the salinity-stressed seedlings, and helped to maintain a lower Na+/K+ ratio in all plant organs, compared with that in the non-pretreated seedlings, possibly by regulating the expression of some important Na+ transporter-encoding genes (OsHKT2;1, OsCNGC1, OsSOS1). Higher levels of lipid peroxidation and hydrogen peroxide (H2O2) concentrations were observed in the shoots of the salinity-stressed seedlings; however, lower levels of lipid peroxidation and H2O2 concentration were detected in the Apigenin-treated seedlings. Apigenin pretreatment was associated with the induction of the rice antioxidant defense system represented by the induced activities of the antioxidant enzymes Catalase (CAT) and Ascorbate peroxidase (APX) in the roots, as well as by increased accumulation of the non-enzymatic antioxidants carotenoids and flavonoids in the shoots, relative to that in the untreated seedlings, under salinity stress conditions. Together, these results suggest that Apigenin pretreatment can alleviate the damaging effects of salinity on rice seedlings, presumably by regulating selective ion uptake by the roots and translocation to the shoots, thereby maintaining higher K+/Na+ ratios critical for normal plant growth under salinity stress, and by triggering the induction of the antioxidant defense system.

Chapter 33 - Episodic ataxias

The familial episodic ataxias (EAs) are prototypical channelopathies in the central nervous system clinically characterized by attacks of imbalance and incoordination variably associated with progressive ataxia and variable interictal features. EA1, EA2, and EA6 are caused by mutations in ion channel- and transporter-encoding genes that regulate neuronal excitability and neurotransmission.

New roles of NO TRANSMITTING TRACT and SEEDSTICK during medial domain development in Arabidopsis fruits.

The gynoecium, the female reproductive part of the flower, is key for plant sexual reproduction. During its development, inner tissues such as the septum and the transmitting tract tissue, important for pollen germination and guidance, are formed. In Arabidopsis, several transcription factors are known to be involved in the development of these tissues. One of them is NO TRANSMITTING TRACT (NTT), essential for transmitting tract formation. We found that the NTT protein can interact with several gynoecium-related transcription factors, including several MADS-box proteins, such as SEEDSTICK (STK), known to specify ovule identity. Evidence suggests that NTT and STK control enzyme and transporter-encoding genes involved in cell wall polysaccharide and lipid distribution in gynoecial medial domain cells. The results indicate that the simultaneous loss of NTT and STK activity affects polysaccharide and lipid deposition and septum fusion, and delays entry of septum cells to their normal degradation program. Furthermore, we identified KAWAK, a direct target of NTT and STK, which is required for the correct formation of fruits in Arabidopsis These findings position NTT and STK as important factors in determining reproductive competence.

Transporters Related to Stress Responses and Their Potential Application in Synechocystis sp. PCC 6803.

Cyanobacteria are autotrophic prokaryotes that can perform oxygenic photosynthesis. The conversion of light and carbon dioxide into green fuels and chemicals has drawn considerable interest, and several dozen products have been successfully synthesized in genetically engineered cyanobacteria. However, during cultivation, cyanobacterial cells are typically exposed to various stresses from the environment, such as acid, salt and metal stresses, as well as from the end products they synthesize, such as ethanol, butanol, and 3-hydroxypropionic acid (3-HP). These stresses hinder the accumulation of biomass and the production of chemicals or biofuels in cyanobacteria. Thus, improving the ability of cyanobacterial cells to resist stress can potentially enhance the robustness of the cyanobacterial chassis and the final yield of the target products. Toward this goal, research has been performed to explore the mechanisms by which cyanobacteria respond to various environmental perturbations and product toxicity. Among these mechanisms, transporters are membrane proteins involved in the transportation of ions, small molecules, or macromolecules across the membrane, and they have been reported to be involved in the response to common stresses in many organisms. Thus, engineering transporter-encoding genes may be a promising solution to increase the resistance of the cells against biotic and abiotic stresses. This chapter focuses on recent progress on the use of transporters related to stress responses in the model cyanobacterium Synechocystis sp. PCC 6803 and presents an updated review of their functions in stress regulation and their potential application in future chassis modifications.

Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling

Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.

Establishment of the Inducible Tet-On System for the Activation of the Silent Trichosetin Gene Cluster in Fusarium fujikuroi.

The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly related to the notorious rice pathogen Fusarium fujikuroi. Here we present the activation and characterization of a homologous, but silent, gene cluster in F. fujikuroi. Bioinformatic analysis revealed that this cluster does not contain the equisetin N-methyltransferase gene eqxD and consequently, trichosetin was isolated as final product. The adaption of the inducible, tetracycline-dependent Tet-on promoter system from Aspergillus niger achieved a controlled overproduction of this toxic metabolite and a functional characterization of each cluster gene in F. fujikuroi. Overexpression of one of the two cluster-specific transcription factor (TF) genes, TF22, led to an activation of the three biosynthetic cluster genes, including the PKS-NRPS key gene. In contrast, overexpression of TF23, encoding a second Zn(II)2Cys6 TF, did not activate adjacent cluster genes. Instead, TF23 was induced by the final product trichosetin and was required for expression of the transporter-encoding gene MFS-T. TF23 and MFS-T likely act in consort and contribute to detoxification of trichosetin and therefore, self-protection of the producing fungus.

The low affinity glucose transporter HxtB is also involved in glucose signalling and metabolism in Aspergillus nidulans

One of the drawbacks during second-generation biofuel production from plant lignocellulosic biomass is the accumulation of glucose, the preferred carbon source of microorganisms, which causes the repression of hydrolytic enzyme secretion by industrially relevant filamentous fungi. Glucose sensing, subsequent transport and cellular signalling pathways have been barely elucidated in these organisms. This study therefore characterized the transcriptional response of the filamentous fungus Aspergillus nidulans to the presence of high and low glucose concentrations under continuous chemostat cultivation with the aim to identify novel factors involved in glucose sensing and signalling. Several transcription factor- and transporter-encoding genes were identified as being differentially regulated, including the previously characterized glucose and xylose transporter HxtB. HxtB was confirmed to be a low affinity glucose transporter, localizing to the plasma membrane under low- and high-glucose conditions. Furthermore, HxtB was shown to be involved in conidiation-related processes and may play a role in downstream glucose signalling. A gene predicted to encode the protein kinase PskA was also identified as being important for glucose metabolism. This study identified several proteins with predicted roles in glucose metabolic processes and provides a foundation for further investigation into the response of biotechnologically important filamentous fungi to glucose.

Awake1, an ABC-Type Transporter, Reveals an Essential Role for Suberin in the Control of Seed Dormancy.

The mother plant plays an important dynamic role in the control of dormancy of her progeny seed in response to environmental signals. In order to further understand the mechanisms by which this dormancy control takes place in Arabidopsis (Arabidopsis thaliana), we conducted a forward genetic screen to isolate mutants that fail to enter dormancy in response to variation in temperature during seed set. We show that, for the first of these mutants, designated awake1, the maternal allele is required for entry into strongly dormant states and that awake1 mutants show seed phenotypes shown previously to be associated with the loss of suberin in the seed. We identify awake1 as an allele of ABCG20, an ATP-binding cassette transporter-encoding gene required for the transport of fatty acids during suberin deposition, and show that further suberin-deficient mutants have seed dormancy defects. Seed coat suberin composition is affected by temperature during seed maturation, but this response appears to be independent of ABCG20. We conclude that seed coat suberin is essential for seed dormancy imposition by low temperature and that the exclusion of oxygen and water from the seed by the suberin and tannin layers is important for dormancy imposition.

Mechanism of formate-nitrite transporters by dielectric shift of substrate acidity.

Bacterial formate-nitrite transporters (FNTs) regulate the metabolic flow of small, weak mono-acids. Recently, the eukaryotic PfFNT was identified as the malaria parasite's lactate transporter and novel drug target. Despite crystal data, central mechanisms of FNT gating and transport remained unclear. Here, we show elucidation of the FNT transport mechanism by single-step substrate protonation involving an invariant lysine in the periplasmic vestibule. Opposing earlier gating hypotheses and electrophysiology reports, quantification of total uptake by radiolabeled substrate indicates a permanently open conformation of the bacterial formate transporter, FocA, irrespective of the pH Site-directed mutagenesis, heavy water effects, mathematical modeling, and simulations of solvation imply a general, proton motive force-driven FNT transport mechanism: Electrostatic attraction of the acid anion into a hydrophobic vestibule decreases substrate acidity and facilitates protonation by the bulk solvent. We define substrate neutralization by proton transfer for transport via a hydrophobic transport path as a general theme of the Amt/Mep/Rh ammonium and formate-nitrite transporters.

Multiple transporters are involved in natamycin efflux in Streptomyces chattanoogensis L10.

Antibiotic-producing microorganisms have evolved several self-resistance mechanisms to prevent auto-toxicity. Overexpression of specific transporters to improve the efflux of toxic antibiotics has been found one of the most important and intrinsic resistance strategies used by many Streptomyces strains. Inthis work, two ATP-binding cassette (ABC) transporter-encoding genes located in the natamycin biosynthetic gene cluster, scnA and scnB, were identified as the primary exporter genes for natamycin efflux in Streptomyces chattanoogensis L10. Two other transporters located outside the cluster, a major facilitator superfamily transporter Mfs1 and an ABC transporter NepI/II were found to play a complementary role in natamycin efflux. ScnA/ScnB and Mfs1 also participate in exporting the immediate precursor of natamycin, 4,5-de-epoxynatamycin, which is more toxic to S. chattanoogensis L10 than natamycin. As the major complementary exporter for natamycin efflux, Mfs1 is up-regulated in response to intracellular accumulation of natamycin and 4,5-de-epoxynatamycin, suggesting a key role in the stress response for self-resistance. This article discusses a novel antibiotic-related efflux and response system in Streptomyces, as well as a self-resistance mechanism in antibiotic-producing strains.

Small Animal Aspergillosis and Cryptococcosis in Japan

Canine and feline upper respiratory tract (URT) infection due to Aspergillus spp. is considered an emerging disease, with the number of reported cases continuing to rise in Japan. Aspergillus fumigatus has been the most frequently reported etiologic agent of sino-orbital aspergillosis in dogs and cats; the other Aspergillus species, Aspergillus felis, Aspergillus fischeri, Aspergillus udagawae, Aspergillus viridinutans, and A. fumigatus, have also been implicated in feline cases. The minimum inhibitory concentrations (MICs) of antifungal drugs are elevated for these cryptic species compared with A. fumigatus. Some reports showed that the feline infections due to cryptic species did not respond to treatment with antifungal drugs. These results suggest that species identification and antifungal susceptibility testing of infecting agents are important to ensure effective treatment of feline URT aspergillosis. Feline cryptococcosis in Japan is typically attributed to Cryptococcus neoformans var. grubii. We isolated a fluconazole-resistant strain of C. grubii from a feline cryptococcosis. The predicted amino acid sequence of the lanosterol 14-α demethylase gene (ERG11) protein in the isolate was identical to that of the C. grubii reference strain. RT-PCR analysis of ERG11 and ATP binding cassette (ABC) transporter-encoding gene (AFR1) indicated that the isolate had increased transcription factor function for ERG11 and AFR1 compared with fluconazole-susceptible strains. This observation, in combination with the lack of resistance to other azoles (that is, lack of cross resistance), suggests that resistance in our isolate was the result of overexpression of the endogenous ERG11 and ABC transporter. Further ecological and epidemiological studies on small animal mycoses in Japan are needed to monitor the emergence of antifungal drug resistant strains.

Aspergillus oryzae nrtA affects kojic acid production.

We analyzed the role of the nitrate transporter-encoding gene (nrtA) of Aspergillus oryzae by gene disruption. Southern hybridization analysis indicated that homologous recombination occurred at the resident nrtA locus. Real-time PCR showed that the nrtA gene was strongly inducible by NaNO3. The nrtA disruptant did not exhibit normal growth when nitrate was available as the sole nitrogen source. These results indicate that NrtA is essential for nitrate uptake in A. oryzae. Kojic acid (KA) production was inhibited by the addition of a small amount of sodium nitrate. The nrtA-disrupted strain was deficient in the uptake of nitrate. As a result, KA production in this strain was not considerably affected by the presence of nitrate.

Relevance of the transcription factor PdSte12 in Penicillium digitatum conidiation and virulence during citrus fruit infection

Green mould, resulting from Penicillium digitatum, is the most important postharvest disease of citrus. In a previous study, the PdSte12 transcription factor gene was identified, and disruption mutants were obtained. In the present study, the ΔPdSte12 mutants generated through gene replacement showed significantly reduced virulence during citrus fruit infection. Virulence was affected not only in mature fruit but also in immature fruit, and disease severity was markedly reduced when the oranges were stored at 20 or 4°C. In addition, the ΔPdSte12 mutants were defective in asexual reproduction, producing few conidia. The conidiophores of these mutants had longer metulae with fewer branches at the tip of the hyphae. Gene expression analysis revealed that PdSte12 might act as a negative regulator of several transporter-encoding genes and a positive regulator of two sterol demethylases, all of which are involved in fungicide resistance and fungal virulence. Moreover, PdSte12 exhibited the negative regulation of another transcription factor PdMut3, putatively involved in fungal pathogenesis but with no effect on the MAPK SLT2 P. digitatum orthologue belonging to different transcription pathways relevant to cell integrity. These results indicate the PdSte12 transcription factor is functionally conserved in P. digitatum for infection and asexual reproduction, similar to other Ste12 fungal plant pathogens.

Causes and Consequences of Variability in Drug Transporter Activity in Pediatric Drug Therapy.

Drug transporters play a key role in mediating the uptake of endo- and exogenous substances into cells as well as their efflux. Therefore, variability in drug transporter activity can influence pharmaco- and toxicokinetics and be a determinant of drug safety and efficacy. In children, particularly in neonates and young infants, the contribution of tissue-specific drug transporters to drug absorption, distribution, and excretion may differ from that in adults. In this review 5 major factors and their interdependence that may influence drug transporter activity in children are discussed: developmental differences, genetic polymorphisms, pediatric comorbidities, interacting comedication, and environmental factors. Even if data are sparse, altered drug transporter activity due to those factors have been associated with clinically relevant differences in drug disposition, efficacy, and safety in pediatric patients. Single nucleotide polymorphisms in drug transporter-encoding genes were the most studied source of drug transporter variability in children. However, in the age group where drug transporter activity has been reported to differ from that in adults, namely neonates and young infants, hardly any studies have been performed. Longitudinal studies in this young population are required to investigate the age- and disease-dependent genotype-phenotype relationships and relevance of drug transporter drug-drug interactions. Physiologically based pharmacokinetic modeling approaches can integrate drug- and patient-specific parameters, including drug transporter ontogeny, and may further improve in silico predictions of pediatric-specific pharmacokinetics.

Functional definition of BirA suggests a biotin utilization pathway in the zoonotic pathogen Streptococcus suis.

Biotin protein ligase is universal in three domains of life. The paradigm version of BPL is the Escherichia coli BirA that is also a repressor for the biotin biosynthesis pathway. Streptococcus suis, a leading bacterial agent for swine diseases, seems to be an increasingly-important opportunistic human pathogen. Unlike the scenario in E. coli, S. suis lacks the de novo biotin biosynthesis pathway. In contrast, it retains a bioY, a biotin transporter-encoding gene, indicating an alternative survival strategy for S. suis to scavenge biotin from its inhabiting niche. Here we report functional definition of S. suis birA homologue. The in vivo functions of the birA paralogue with only 23.6% identity to the counterpart of E. coli, was judged by its ability to complement the conditional lethal mutants of E. coli birA. The recombinant BirA protein of S. suis was overexpressed in E. coli, purified to homogeneity and verified with MS. Both cellulose TLC and MALDI-TOFF-MS assays demonstrated that the S. suis BirA protein catalyzed the biotinylation reaction of its acceptor biotin carboxyl carrier protein. EMSA assays confirmed binding of the bioY gene to the S. suis BirA. The data defined the first example of the bifunctional BirA ligase/repressor in Streptococcus.

A putative magnesium transporter Slr1216 involved in sodium tolerance in cyanobacterium Synechocystis sp. PCC 6803

In the model cyanobacterium Synechocystis sp. PCC 6803, the details of cellular response networks to high and fluctuating salinity are not immediately available. In this study, by screening gene knockout mutants of 58 Synechocystis transporter-encoding genes under salt stress, we found the mutant of slr1216, annotated as a magnesium transporter-encoding gene in Cyanobase, was less tolerant to salt than the wild type. Meanwhile, the tolerance loss can be recovered to the similar level of the wild type by complementing the slr1216 gene to the ∆slr1216 mutant, suggesting that slr1216 may be involved in salt tolerance in Synechocystis. The following GC–MS analysis showed that the content of glucosylglycerol (GG), one major compatible solute against salt stress, was lower in the ∆slr1216 mutant than that of the wild type, while the GG content was also recovered to a similar level of the wild type in the complementation strain. In addition, the positive effect of exogenously provided GG on growth of the ∆slr1216 mutant under salt stress was observed. Together, the results showed the transporter Slr1216 might be involved in salt tolerance by affecting intracellular GG concentration, which provided new insight into the complex cellular response networks to salt stress in Synechocystis.

Deciphering a unique biotin scavenging pathway with redundant genes in the probiotic bacterium Lactococcus lactis.

Biotin protein ligase (BPL) is widespread in the three domains of the life. The paradigm BPL is the Escherichia coli BirA protein, which also functions as a repressor for the biotin biosynthesis pathway. Here we report that Lactococcus lactis possesses two different orthologues of birA (birA1_LL and birA2_LL). Unlike the scenario in E. coli, L. lactis appears to be auxotrophic for biotin in that it lacks a full biotin biosynthesis pathway. In contrast, it retains two biotin transporter-encoding genes (bioY1_LL and bioY2_LL), suggesting the use of a scavenging strategy to obtain biotin from the environment. The in vivo function of the two L. lactis birA genes was judged by their abilities to complement the conditional lethal E. coli birA mutant. Thin-layer chromatography and mass spectroscopy assays demonstrated that these two recombinant BirA proteins catalyze the biotinylation reaction of the acceptor biotin carboxyl carrier protein (BCCP), through the expected biotinoyl-AMP intermediate. Gel shift assays were used to characterize bioY1_LL and BirA1_LL. We also determined the ability to uptake 3H-biotin by L. lactis. Taken together, our results deciphered a unique biotin scavenging pathway with redundant genes present in the probiotic bacterium L. lactis.

Towards "biophysical psychiatry": a modeling approach for studying effects of schizophrenia-linked genes on single-neuron excitability

Genome-wide association studies (GWAS) employing large sample sizes and sophisticated statistical methods have recently yielded detailed information on the set of genes affected in various psychiatric disorders. This is especially important for polygenic, highly heritable disorders such as schizophrenia (SCZ) [1]. The success lately witnessed in gene discovery brings up the next big challenge for psychiatric genetics - translation of the genetic associations into biological insights [2]. In this study, we propose a computational approach for investigating the effects of a collection of excitability-related genes on various neuronal characteristics. As a proof of principle, we apply our approach for studying effects of SCZ-linked genes on firing behavior of a layer V pyramidal cell (L5PC). A total of 108 genetic loci were recently confirmed to be associated with the risk of SCZ [3]. These loci span a wide set of protein-coding genes. The disorder is associated with genes affecting transmembrane currents of all major cationic species, Na+, K+, and Ca2+. In addition, some of the SCZ-linked genes are involved in regulation of the Ca2+ concentration in the intracellular medium, which is another great contributor to neuron excitability. All above aspects of electrophysiology are included in a recent multi-compartmental model of L5PC [4], which accurately describes the perisomatic firing behavior and its interplay with the generation of an apical Ca2+ spike. In this work, we rely on data from functional genomics studies that describe the effects of variants of certain ion channel or calcium transporter-encoding genes on the channel activation/inactivation properties or intracellular Ca2+ dynamics. We carry out our study by linking these effects to a change in the corresponding neuron model parameters, and observing the implication that these variants have on the information integration in an L5PC. It should be noted that information does not generally exist for the effect of single nucleotide polymorphism (SNP) variants identified through GWASs on the parameters required for the computational models. We instead use information obtained from in vitro studies of more extreme genetic variations, including loss of function mutations. A central assumption of this approach is that the effects of SNP variants can be represented as scaled-down versions of those of the more extreme variants, and that the emergence of the full psychiatric disease phenotype results from the combined effect of a large number of subtle SNP effects. Our results show a multitude of alterations of the firing behavior and integration of apical stimuli in neurons equipped with the considered gene variants. An especially interesting observation is that the variants affect the suppression of a second apical stimulus, which might have a connection with the deficit in prepulse inhibition, a condition often observed in SCZ patients. Although the analyses presented here are specific to L5PCs and SCZ-related genes, our biophysical psychiatry framework may be directly applicable to other cell types and other polygenic diseases, such as bipolar disorder and autism, given an identification of risk genes related to neuronal excitability. Furthermore, our approach could be directly applied to biophysically detailed models of neuronal networks and extended to consider synaptic ion channel-encoding genes that are relevant in SCZ [5].