Current research in physiology最新文献

{"title":"Does the ventricle limit cardiac contraction rate in the anoxic turtle (Trachemys scripta)? I. Comparison of the intrinsic contractile responses of cardiac chambers to the extracellular changes that accompany prolonged anoxia exposure","authors":"Molly Garner,&nbsp;Jonathan A.W. Stecyk","doi":"10.1016/j.crphys.2022.07.001","DOIUrl":"10.1016/j.crphys.2022.07.001","url":null,"abstract":"<div><p>Multiple lines of evidence suggest that an inability of the ventricle to contract in coordination with the pacemaker during anoxia exposure may suppress cardiac pumping rate in anoxia-tolerant turtles. To determine under what extracellular conditions the ventricle could be the weak link that limits cardiac pumping, we compared, under various extracellular conditions, the intrinsic contractile properties of isometrically-contracting ventricular and atrial strips obtained from 21 °C- to 5 °C- acclimated turtles (<em>Trachemys scripta</em>) that had been exposed to either normoxia or anoxia (16 h at 21 °C; 12 days at 5 °C). We found that combined extracellular anoxia, acidosis, and hyperkalemia (AAK), severely disrupted ventricular, but not right or left atrial, excitability and contractibility of 5 °C anoxic turtles. However, combined hypercalcemia and heightened adrenergic stimulation counteracted the negative effects of AAK. We also report that the turtle heart is resilient to prolonged diastolic intervals, which would ensure that contractile force is maintained if arrhythmia were to occur during anoxia exposure. Finally, our findings reinforce that prior temperature and anoxia experiences are central to the intrinsic contractile response of the turtle myocardium to altered extracellular conditions. At 21 °C, prior anoxia exposure preconditioned the ventricle for anoxic and acidosis exposure. At 5 °C, prior anoxia exposure evoked heightened sensitivity of the ventricle to hyperkalemia, as well as all chambers to combined hypercalcemia and increased adrenergic stimulation. Overall, our findings show that the ventricle could limit cardiac pumping rate during prolonged anoxic submergence in cold-acclimated turtles if hypercalcemia and heightened adrenergic stimulation are insufficient to counteract the negative effects of combined extracellular anoxia, acidosis, and hyperkalemia.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 312-326"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b5/8a/main.PMC9301509.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40643054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing chicken cardiac muscle mitochondria are resistant to variations in incubation oxygen levels","authors":"Vanessa J. Starr,&nbsp;Edward M. Dzialowski","doi":"10.1016/j.crphys.2022.03.001","DOIUrl":"10.1016/j.crphys.2022.03.001","url":null,"abstract":"<div><h3>Background</h3><p>Chronic exposure to hypoxia during vertebrate development can produce abnormal cardiovascular morphology and function. The aim of this study was to examine cardiac mitochondria function in an avian model, the chicken, in response to embryonic development under hypoxic (15% O₂), normoxic (21% O₂), or hyperoxic (40% O₂) incubation conditions.</p></div><div><h3>Methods</h3><p>Chicken embryos were incubated in hypoxia, normoxia, or hyperoxia beginning on day 5 of incubation through hatching. Cardiac mitochondria oxygen flux and reactive oxygen species production were measured in permeabilized cardiac fibers from externally pipped and 1-day post hatchlings.</p></div><div><h3>Results</h3><p>Altering oxygen during development had a large effect on body and heart masses of externally pipped embryos and 1-day old hatchlings. Hypoxic animals had smaller body masses and absolute heart masses, but proportionally similar sized hearts compared to normoxic animals during external pipping. Hyperoxic animals were larger with larger hearts than normoxic animals during external pipping. Mitochondrial oxygen flux in permeabilized cardiac muscle fibers revealed limited effects of developing under altered oxygen conditions, with only oxygen flux through cytochrome oxidase being lower in hypoxic hearts compared with hyperoxic hearts. Oxygen flux in leak and oxidative phosphorylation states were not affected by developmental oxygen levels. Mitochondrial reactive oxygen species production under leak and oxidative phosphorylation states studied did not differ between any developmental oxygen treatment.</p></div><div><h3>Conclusions</h3><p>These results suggest that cardiac mitochondria function of the developing chicken is not altered by developing <em>in ovo</em> under different oxygen levels.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 151-157"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266594412200013X/pdfft?md5=4cc66a65a75dceb5f8f67e2c263b3e8e&pid=1-s2.0-S266594412200013X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46181240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carotid artery vasoreactivity correlates with abdominal aortic vasoreactivity in young healthy individuals but not in patients with abdominal aortic aneurysm","authors":"Jenske J.M. Vermeulen ,&nbsp;Anne-Jet S. Jansen ,&nbsp;Sam van de Sande ,&nbsp;Yvonne A.W. Hartman ,&nbsp;Suzanne Holewijn ,&nbsp;Michel M.P.J. Reijnen ,&nbsp;Dick H.J. Thijssen","doi":"10.1016/j.crphys.2022.05.004","DOIUrl":"10.1016/j.crphys.2022.05.004","url":null,"abstract":"<div><h3>Background</h3><p>Sympathetic stimulation of central arteries, such as coronary and carotid arteries, cause vasodilation in healthy subjects, but vasoconstriction in those with increased cardiovascular risk. This study compared vasoreactivity to sympathetic stimulation between abdominal aorta and carotid artery in healthy young individuals (young group, n = 20), in patients with abdominal aortic aneurysm (AAA group, n = 20) and in a healthy older group, age- and gender matched with AAA group (matched group, n = 18).</p></div><div><h3>Method</h3><p>All subjects underwent cold pressor test, while performing concomitantly duplex ultrasound of abdominal aorta and carotid artery vasoreactivity. Observer-independent software was used to analyze and calculate magnitude and timing of maximum vasodilation or vasoconstriction. Pearson's correlation coefficient was calculated to investigate vasoreactivity between arteries.</p></div><div><h3>Results</h3><p>Carotid artery reactivity [Interquartile range 25%, Interquartile range 75%] did not significantly differ between the young, matched and AAA group (3.5% [1.4, 4.7], 2.6% [2.0, 4.1] and 2.2% [-1.9, 3.7], respectively, p = 0.301). Abdominal aortic responsiveness demonstrated larger differences between young (4.9% [-0.2, 8.4]), matched (3.3% [-2.5, 4.4]) and individuals with AAA (0.5% [-3.9, 4.1], p = 0.059). Pooled analysis showed a significant correlation between carotid and abdominal aortic vasoreactivity (r = 0.444, p = 0.001). Subgroup analyses demonstrated significant correlation between both arteries in young (r = 0.636, p = 0.003), but not matched (r = −0.040, p = 0.866) or AAA group (r = 0.410, p = 0.129).</p></div><div><h3>Conclusions</h3><p>Sympathetic stimulation induces powerful vasodilation of the carotid artery and abdominal aorta, which is significantly correlated in healthy individuals. No such correlation is present in abdominal aortic aneurysm patients. This suggests the aneurysm alters local abdominal aorta vasoreactivity, but not the carotid artery.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 224-231"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665944122000232/pdfft?md5=4b4cc91a7f8a95a7064b8ad238e2f79e&pid=1-s2.0-S2665944122000232-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48211955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhythmicity in heart rate and its surges usher a special period of sleep, a likely home for PGO waves","authors":"Andreas A. Ioannides ,&nbsp;Gregoris A. Orphanides ,&nbsp;Lichan Liu","doi":"10.1016/j.crphys.2022.02.003","DOIUrl":"10.1016/j.crphys.2022.02.003","url":null,"abstract":"<div><p>High amplitude electroencephalogram (EEG) events, like unitary K-complex (KC), are used to partition sleep into stages and hence define the hypnogram, a key instrument of sleep medicine. Throughout sleep the heart rate (HR) changes, often as a steady HR increase leading to a peak, what is known as a heart rate surge (HRS). The hypnogram is often unavailable when most needed, when sleep is disturbed and the graphoelements lose their identity. The hypnogram is also difficult to define during normal sleep, particularly at the start of sleep and the periods that precede and follow rapid eye movement (REM) sleep. Here, we use objective quantitative criteria that group together periods that cannot be assigned to a conventional sleep stage into what we call REM0 periods, with the presence of a HRS one of their defining properties. Extended REM0 periods are characterized by highly regular sequences of HRS that generate an infra-low oscillation around 0.05 Hz. During these regular sequence of HRS, and just before each HRS event, we find avalanches of high amplitude events for each one of the mass electrophysiological signals, i.e. related to eye movement, the motor system and the general neural activity. The most prominent features of long REM0 periods are sequences of three to five KCs which we label multiple K-complexes (KCm). Regarding HRS, a clear dissociation is demonstrated between the presence or absence of high gamma band spectral power (55–95 Hz) of the two types of KCm events: KCm events with strong high frequencies (KCmWSHF) cluster just before the peak of HRS, while KCm between HRS show no increase in high gamma band (KCmNOHF). Tomographic estimates of activity from magnetoencephalography (MEG) in pre-KC periods (single and multiple) showed common increases in the cholinergic Nucleus Basalis of Meynert in the alpha band. The direct contrast of KCmWSHF with KCmNOHF showed increases in all subjects in the high sigma band in the base of the pons and in three subjects in both the delta and high gamma bands in the medial Pontine Reticular Formation (mPRF), the putative Long Lead Initial pulse (LLIP) for Ponto-Geniculo-Occipital (PGO) waves.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 118-141"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8867048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45045190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of chest mobilization on intercostal muscle stiffness","authors":"Yu Yokoyama ,&nbsp;Taiki Kodesho ,&nbsp;Takuya Kato ,&nbsp;Gakuto Nakao ,&nbsp;Yuhei Saito ,&nbsp;Keigo Taniguchi","doi":"10.1016/j.crphys.2022.10.002","DOIUrl":"10.1016/j.crphys.2022.10.002","url":null,"abstract":"<div><p>This study examined the effect of chest mobilization on intercostal (IC) muscle stiffness using the IC muscle shear modulus. Sixteen healthy young men participated on two days with a minimum of 24 h between the stretching and control conditions (SC and CC). The tasks were resting breathing and deep breathing. The IC muscle shear modulus and muscle activity and rib cage circumference were measured before and after each condition. In the SC, IC stretching was performed for 1 min x 5 sets. In the CC, resting breathing, in a sitting position, was performed for 5 min. In the SC, the IC muscle shear modulus decreased significantly (p &lt; 0.05) at maximum inspiration in the deep breathing task, but there was no significant difference in the CC pre- and post-intervention. The results suggest that IC muscle stretching decreases IC muscle stiffness and improves muscle flexibility and that the IC muscle shear modulus may measure the effectiveness of chest mobilization.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 429-435"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/55/0d/main.PMC9713255.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35254875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis of temperature-dependent developmental plasticity within the ventricle of juvenile Atlantic salmon (Salmo salar)","authors":"Carlie A. Muir,&nbsp;Bradley S. Bork,&nbsp;Bryan D. Neff,&nbsp;Sashko Damjanovski","doi":"10.1016/j.crphys.2022.07.005","DOIUrl":"10.1016/j.crphys.2022.07.005","url":null,"abstract":"<div><p>In teleosts, cardiac plasticity plays a central role in mediating thermal acclimation. Previously, we demonstrated that exposure to elevated temperatures throughout development (+4°C) improved acute thermal tolerance of the heart in juvenile Atlantic salmon. Fish raised in a warmer thermal regime also displayed higher proportions of compact myocardium within their ventricles. In the present study, we investigated the molecular mechanisms supporting this temperature-specific phenotype by comparing relative protein abundance in ventricular tissue from the same experimental fish using mass spectrometry. We provide the first description of the ventricular proteome in juvenile Atlantic salmon and identify 79 proteins displaying differential abundance between developmental treatments. The subset of proteins showing higher abundance in fish raised under elevated temperatures was significantly enriched for processes related to ventricular tissue morphogenesis, and changes in protein abundance support a hypertrophic model of compact myocardium growth. Proteins associated with the vasculature and angiogenesis also showed higher abundance in the warm-developmental group, suggesting capillarization of the compact myocardium in the hearts of these fish. Proteins related to oxidative metabolism and protein homeostasis also displayed substantive shifts in abundance between developmental treatments, underscoring the importance of these processes in mediating thermal plasticity of cardiac function. While rapid growth under warm developmental temperatures has been linked to cardiomyopathies in farmed salmon, markers of cardiac pathology were not implicated in the present study. Thus, our findings offer a molecular footprint for adaptive temperature-dependent plasticity within the ventricle of a juvenile salmonid.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 344-354"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/06/ac/main.PMC9403292.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33444855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of combined aerobic and resistance exercise on serum Klotho secretion in healthy young men -a pilot study-","authors":"Takuma Morishima ,&nbsp;Eisuke Ochi","doi":"10.1016/j.crphys.2022.06.001","DOIUrl":"10.1016/j.crphys.2022.06.001","url":null,"abstract":"<div><p>The impact of combined aerobic and resistance exercise on Klotho (KL) secretion is unclear. Twelve healthy young men completed two randomized experimental trials: 1) resistance exercise (RE) and 2) resistance exercise with prior aerobic exercise (AE + RE). Following baseline blood pressure assessment and blood collection, the subjects in the RE trial maintained a supine position for 45 min, while the subjects in the AE + RE trial performed 45 min of aerobic exercise. After 45 min of resting or aerobic exercise, all subjects performed resistance exercise. Following resistance exercise, the subjects rested in a supine position for 60 min. Blood pressure assessment and blood collection were repeated. Aerobic and resistance exercise significantly increased serum KL concentrations, respectively (P &lt; 0.05), and no additive effect of aerobic exercise on KL secretion was observed immediately after resistance exercise in the AE + RE trial compared with the RE trial. However, serum KL levels at 30 and 60 min after resistance exercise were significantly higher in the AE + RE trial than in the RE trial. Serum ET-1 concentrations were significantly increased only in the RE trial. In conclusion, combined aerobic and resistance exercise could maintain higher levels of serum KL secretion after exercise compared with resistance exercise only.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 246-250"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0e/8a/main.PMC9218281.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40400823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skipping the first active meal appears to adversely alter reproductive function in female than male rats","authors":"Oluwakemi T. Oyelowo,&nbsp;Emmanuel O. Taire,&nbsp;Olubunmi I. Ajao","doi":"10.1016/j.crphys.2022.10.001","DOIUrl":"10.1016/j.crphys.2022.10.001","url":null,"abstract":"<div><p>There is a growing consciousness about chrono-nutrition and its physiological functions. The human feeding pattern establishes three meals a day, meal timing however may not be adhered to. Previous studies have reported ovarian dysfunctions in breakfast skipping among females. In this study, the investigation was carried out on the effects of breakfast skipping on reproductive functions in the male rat and comparison, to the female rat. Eight-week-old animals (10 rats per group) were used to mimic post-adolescence. Rats are active at night thus the meal model was divided as follows. Female rats who had all three meals (Control_F), Female rats who had a no-first-active meal (NFAM_F), Male rats who had all three meals (Control_M), and Male rats who had a no-first-active meal (NFAM_M). All animals were fed the same amount of food every day. After the expiration of the four weeks experiment, serum testosterone, estrogen, Luteinising Hormone (LH) Follicle Stimulating Hormone (FSH), and prolactin (PRL) were quantified using ELISA. Sperm was also analyzed. There was a significant increase (p &lt; 0.05) in the testosterone level and sperm count in the NFAM_M compared to the Control_M while the estrogen level was significantly reduced in the NFAM_F compared to the Control_F. LH, FSH, and PRL levels were significantly reduced in the NFAM_F compared to the NFAM_M. These findings further confirm that post-adolescent females are prone to breakfast skipping. The increase in testosterone levels and sperm count in the males establish that breakfast skipping might not interfere with the reproductive physiology in males as it does in females.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 414-420"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3f/1e/main.PMC9576489.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40561805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucose uptake as an alternative to oxygen uptake for assessing metabolic rate in Danio rerio larvae","authors":"Bridget L. Evans ,&nbsp;Adam F.L. Hurlstone ,&nbsp;Peter E. Clayton ,&nbsp;Adam Stevens ,&nbsp;Holly A. Shiels","doi":"10.1016/j.crphys.2022.05.002","DOIUrl":"10.1016/j.crphys.2022.05.002","url":null,"abstract":"<div><p>Respirometry, based on oxygen uptake, is commonly employed for measuring metabolic rate. There is a growing need for metabolic rate measurements suitable for developmental studies, particularly in <em>Danio rerio</em>, where many important developmental stages occur at &lt; 4 mm. However, respirometry becomes more challenging as the size of the organism reduces. Additionally, respirometry can be costly and require significant experience and technical knowledge which may prohibit uptake in non-specialist/non-physiology labs. Thus, using equipment routine in most developmental/molecular biology laboratories, we measured glucose uptake in 96-h post fertilisation (hpf) zebrafish larvae and compared it to stop-flow respirometry measures of oxygen uptake to test whether glucose uptake was a suitable alternative measure of metabolic rate. A Passing-Bablok regression revealed that within a 95% limit of agreement, the rate of glucose uptake and the rate of oxygen uptake were equivalent as measures of metabolic rate in 96 hpf <em>Danio rerio</em> larvae. Thus, the methodology we outline here may be a useful alternative or a complementary method for assessing metabolic rate in small organisms.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 216-223"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665944122000219/pdfft?md5=6901516fc7155a449eab9603dba411a5&pid=1-s2.0-S2665944122000219-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43733117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of an autism-associated KCNMB2 variant, G124R, on BK channel properties","authors":"Hans J. Moldenhauer ,&nbsp;Ria L. Dinsdale ,&nbsp;Sara Alvarez ,&nbsp;Alberto Fernández-Jaén ,&nbsp;Andrea L. Meredith","doi":"10.1016/j.crphys.2022.09.001","DOIUrl":"10.1016/j.crphys.2022.09.001","url":null,"abstract":"<div><p>BK K⁺ channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the <em>KCNMA1</em> gene and cell- and tissue-selective β subunits (<em>KCNMB1-4</em>). Mutations in <em>KCNMA1</em> are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating. In this study, we report the functional effect of G124R, a novel <em>KCNMB2</em> mutation obtained from whole-exome sequencing of a patient diagnosed with autism spectrum disorder. Residue G124, located in the extracellular loop between TM1 and TM2, is conserved across species, and the G124R missense mutation is predicted deleterious with computational tools. To investigate the pathogenicity potential, BK channels were co-expressed with β2^WT and β2^G124R subunits in HEK293T cells. BK/β2 currents were assessed from inside-out patches under physiological K⁺ conditions (140/6 mM K⁺ and 10 μM Ca²⁺) during activation and inactivation (voltage-dependence and kinetics). Using β2 subunits lacking inactivation (β2IR) revealed that currents from BK/β2IR^G124R channels activated 2-fold faster and deactivated 2-fold slower compared with currents from BK/β2IR^WT channels, with no change in the voltage-dependence of activation (V_1/2). Despite the changes in the BK channel opening and closing, BK/β2^G124R inactivation rates (τ_inact and τ_recovery), and the V_1/2 of inactivation, were unaltered compared with BK/β2^WT channels under standard steady-state voltage protocols. Action potential-evoked current was also unchanged. Thus, the mutant phenotype suggests the β2^G124R TM1-TM2 extracellular loop could regulate BK channel activation and deactivation kinetics. However, additional evidence is needed to validate pathogenicity for this patient-associated variant in <em>KCNMB</em>2.</p></div>","PeriodicalId":72753,"journal":{"name":"Current research in physiology","volume":"5 ","pages":"Pages 404-413"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e6/fe/main.PMC9531041.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33490748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}