Journal of Physiology-London最新文献

{"title":"Kv₄ channels improve the temporal processing of auditory neurons in the cochlear nucleus.","authors":"Chuangeng Zhang, Meijian Wang, Tingting Zhang, Ruili Xie","doi":"10.1113/JP286174","DOIUrl":"https://doi.org/10.1113/JP286174","url":null,"abstract":"<p><p>Kv₄ channels generate A-type current known to regulate neuronal excitability. Its role in processing timing information is understudied, especially in the auditory system where temporal information is crucial for hearing. In the cochlear nucleus, principal bushy neurons are specialized for temporal processing with distinct biophysical properties owing to their expression of various voltage-gated ion channels. Previous studies reported conflicting information regarding the expression and potential role of Kv₄ channels in these neurons. We explored these questions using electrophysiology in CBA/CaJ mice of either sex. A-type current was isolated from 88% of bushy neurons using Kv₄ channel-selective blocker Jingzhaotoxin-X (JZ-X), which increased the intrinsic excitability of bushy neurons without altering their synaptic input. During high-rate activity, JZ-X treatment significantly increased the spike jitter and reduced the firing threshold of bushy neurons. In old mice, A-type current in bushy neurons reduced in magnitude but maintained current density, accompanied by decreased membrane surface area. In contrast, TEA-sensitive Kv₃ current reduced in both magnitude and current density, indicative of a greater contribution to the altered biophysical properties of bushy neurons during ageing. Our findings suggest that Kv₄ channels play significant roles in regulating neuronal excitability and improving the temporal processing of bushy neurons. Such function is likely retained with age and is not the primary mechanism driving compromised temporal processing under age-related hearing loss. KEY POINTS: Most bushy neurons of the cochlear nucleus exhibit Kv₄-mediated A-type current. A-type current regulates neuronal excitability of bushy neurons without contributing to the synaptic transmission at the endbulb of Held. A-type current increases the firing threshold and improves the temporal precision of spikes in bushy neurons during high-rate activity. A-type current reduces peak amplitude in bushy neurons during ageing but maintains current density. Decreased Kv₃ current, rather than Kv₄ current, likely play more significant roles in altering the biophysical properties of bushy neurons during ageing, contributing to compromised temporal processing during age-related hearing loss.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menstrual cycle phase does not influence muscle protein synthesis or whole-body myofibrillar proteolysis in response to resistance exercise.","authors":"Lauren M Colenso-Semple, James McKendry, Changhyun Lim, Philip J Atherton, Daniel J Wilkinson, K Smith, Stuart M Phillips","doi":"10.1113/JP287342","DOIUrl":"https://doi.org/10.1113/JP287342","url":null,"abstract":"<p><p>It has been hypothesised that skeletal muscle protein turnover is affected by menstrual cycle phase with a more anabolic environment during the follicular vs. the luteal phase. We assessed the influence of menstrual cycle phase on muscle protein synthesis and myofibrillar protein breakdown in response to 6 days of controlled resistance exercise in young females during peak oestrogen and peak progesterone, using stable isotopes, unbiased metabolomics and muscle biopsies. We used comprehensive menstrual cycle phase-detection methods, including cycle tracking, blood samples and urinary test kits, to classify menstrual phases. Participants (n = 12) completed two 6 day study phases in a randomised order: late follicular phase and mid-luteal phase. Participants performed unilateral resistance exercise in each menstrual cycle phase, exercising the contralateral leg in each phase in a counterbalanced manner. Follicular phase myofibrillar protein synthesis (MPS) rates were 1.33 ± 0.27% h^-1 in the control leg and 1.52 ± 0.27% h^-1 in the exercise leg. Luteal phase MPS was 1.28 ± 0.27% h^-1 in the control leg and 1.46 ± 0.25% h^-1 in the exercise leg. We observed a significant effect of exercise (P < 0.001) but no effect of cycle phase or interaction. There was no significant effect of menstrual cycle phase on whole-body myofibrillar protein breakdown (P = 0.24). Using unbiased metabolomics, we observed no notable phase-specific changes in circulating blood metabolites associated with any particular menstrual cycle phase. Fluctuations in endogenous ovarian hormones influenced neither MPS, nor MPB in response to resistance exercise. Skeletal muscle is not more anabolically responsive to resistance exercise in a particular menstrual cycle phase. KEY POINTS: It has been hypothesised that the follicular (peak oestrogen) vs. the luteal (peak progesterone) phase of the menstrual cycle is more advantageous for skeletal muscle anabolism in response to resistance exercise. Using best practice methods to assess menstrual cycle status, we measured integrated (over 6 days) muscle protein synthesis (MPS) and myofibrillar protein breakdown (MPB) following resistance exercise in females (n = 12) in their follicular and luteal phases. We observed the expected differences in oestrogen and progesterone concentrations that confirmed our participants' menstrual cycle phase; however, there were no notable metabolic pathway differences, as measured using metabolomics, between cycle phases. We observed that resistance exercise stimulated MPS, but there was no effect of menstrual cycle phase on either resting or exercise-stimulated MPS or MPB. Our data show no greater anabolic effect of resistance exercise in the follicular vs. the luteal phase of the menstrual cycle.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical loading reveals an intrinsic cardiomyocyte stiffness contribution to diastolic dysfunction in murine cardiometabolic disease","authors":"Johannes V. Janssens,&nbsp;Antonia J. A. Raaijmakers,&nbsp;Parisa Koutsifeli,&nbsp;Kate L. Weeks,&nbsp;James R. Bell,&nbsp;Jennifer E. Van Eyk,&nbsp;Claire L. Curl,&nbsp;Kimberley M. Mellor,&nbsp;Lea M. D. Delbridge","doi":"10.1113/JP286437","DOIUrl":"10.1113/JP286437","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 \u0000 &lt;div&gt;Cardiometabolic syndromes including diabetes and obesity are associated with occurrence of heart failure with diastolic dysfunction. There are no specific treatments for diastolic dysfunction, and therapies to manage symptoms have limited efficacy. Understanding of the cardiomyocyte origins of diastolic dysfunction is an important priority to identify new therapeutics. The investigative goal was to experimentally define &lt;i&gt;in vitro&lt;/i&gt; stiffness properties of isolated cardiomyocytes derived from rodent hearts exhibiting diastolic dysfunction &lt;i&gt;in vivo&lt;/i&gt; in response to dietary induction of cardiometabolic disease. Male mice fed a high fat/sugar diet (HFSD &lt;i&gt;vs&lt;/i&gt;. control) exhibited diastolic dysfunction (echo &lt;i&gt;E&lt;/i&gt;/&lt;i&gt;e&lt;/i&gt;′ Doppler ratio). Intact paced cardiomyocytes were functionally investigated in three conditions: non-loaded, loaded and stretched. Mean stiffness of HFSD cardiomyocytes was 70% higher than control. &lt;i&gt;E&lt;/i&gt;/&lt;i&gt;e&lt;/i&gt;′ for the HFSD hearts was elevated by 35%. A significant relationship was identified between &lt;i&gt;in vitro&lt;/i&gt; cardiomyocyte stiffness and &lt;i&gt;in vivo&lt;/i&gt; dysfunction severity. With conversion from the non-loaded to loaded condition, the decrement in maximal sarcomere lengthening rate was more accentuated in HFSD cardiomyocytes (&lt;i&gt;vs&lt;/i&gt;. control). With stretch, the Ca&lt;sup&gt;2+&lt;/sup&gt; transient decay time course was prolonged. With increased pacing, cardiomyocyte stiffness was elevated, yet diastolic Ca&lt;sup&gt;2+&lt;/sup&gt; elevation was attenuated. Our findings show unequivocally that cardiomyocyte mechanical dysfunction cannot be detected by analysis of non-loaded shortening. Collectively, these findings demonstrate that a component of cardiac diastolic dysfunction in cardiometabolic disease is derived from cardiomyocyte stiffness. Differential responses to load, stretch and pacing suggest that a previously undescribed alteration in myofilament–Ca&lt;sup&gt;2+&lt;/sup&gt; interaction contributes to intrinsic cardiomyocyte stiffness in cardiometabolic disease.\u0000\u0000 &lt;figure&gt;\u0000 &lt;div&gt;&lt;picture&gt;\u0000 &lt;source&gt;&lt;/source&gt;&lt;/picture&gt;&lt;p&gt;&lt;/p&gt;\u0000 &lt;/div&gt;\u0000 &lt;/figure&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Understanding cardiomyocyte stiffness components is an important priority for identifying new therapeutics for diastolic dysfunction, a key feature of cardiometabolic disease.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;In this study cardiac function was measured &lt;i&gt;in vivo&lt;/i&gt; (echocardiography) for mice fed a high-fat/sugar diet (HFSD, ≥25 weeks). Performance of intact isolated cardiomyocytes derived from the same hearts was measured during pacing under no","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 24","pages":"6705-6727"},"PeriodicalIF":4.7,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP286437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skeletal and respiratory muscle blood flow redistribution during submaximal exercise in pulmonary hypertensive rats.","authors":"Kiana M Schulze, Ramona E Weber, Andrew G Horn, K Sue Hageman, Nathan J Kenney, Bradley J Behnke, David C Poole, Timothy I Musch","doi":"10.1113/JP287549","DOIUrl":"https://doi.org/10.1113/JP287549","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Pulmonary hypertension (PH) is a chronic, progressive disease characterized by pulmonary vascular remodelling, dyspnoea and exercise intolerance. Key facets of dyspnoea and exercise intolerance include skeletal and respiratory muscle contractile and metabolic disturbances; however, muscle perfusion during exercise has not been investigated. We hypothesized that diaphragm blood flow ( &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) would be increased and locomotory muscle &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; would be decreased during submaximal treadmill running in PH rats compared to healthy controls. Female Sprague-Dawley rats were injected (i.p.) with monocrotaline to induce PH (n = 16), or a vehicle control (n = 15). Disease progression was monitored via echocardiography. When moderate disease severity was confirmed, maximal oxygen uptake ( &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;msup&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;max&lt;/mi&gt;&lt;/msup&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{{{2}^{{mathrm{max}}}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) tests were performed. Rats were given &gt;24 h to recover, and then fluorescent microspheres were infused during treadmill running (20 m/min, 10% grade; ∼40-50% maximal speed attained during the &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;msup&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;max&lt;/mi&gt;&lt;/msup&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{{{2}^{{mathrm{max}}}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; test) to determine tissue &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; . In PH rats compared with healthy controls, &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;msup&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;max&lt;/mi&gt;&lt;/msup&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{{{2}^{{mathrm{max}}}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; was lower (84 (7) vs. 67 (11) ml/min/kg; P &lt; 0.001), exercising diaphragm &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; was 35% higher and soleus &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; was 28% lower. Diaphragm &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; was negatively correlated with soleus &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;annotation&gt;$dot{Q}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; and &lt;math&gt; &lt;semantics&gt; &lt;msub&gt;&lt;mover&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt; &lt;msub&gt;&lt;mi&gt;O&lt;/mi&gt; &lt;msup&gt;&lt;mn&gt;2&lt;/mn&gt; &lt;mi&gt;max&lt;/mi&gt;&lt;/msup&gt; &lt;/msub&gt; &lt;/msub&gt; &lt;annotation&gt;${{dot{V}}_{{{{mathrm{O}}}_{{{2}^{{mathrm{max}}}}}}}}$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; in PH rats. Furthermore, there was regional &lt;math&gt; &lt;semantics&gt;&lt;mover&gt;&lt;mi&gt;Q&lt;/mi&gt; &lt;mo&gt;̇&lt;/mo&gt;&lt;/mover&gt;","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feature selectivity and invariance in marsupial primary visual cortex.","authors":"Young Jun Jung, Ali Almasi, Shi Sun, Molis Yunzab, Sebastien H Baquier, Marilyn Renfree, Hamish Meffin, Michael R Ibbotson","doi":"10.1113/JP285757","DOIUrl":"https://doi.org/10.1113/JP285757","url":null,"abstract":"<p><p>A fundamental question in sensory neuroscience revolves around how neurons represent complex visual stimuli. In mammalian primary visual cortex (V1), neurons decode intricate visual features to identify objects, with most being selective for edge orientation, but with half of those also developing invariance to edge position within their receptive fields. Position invariance allows cells to continue to code an edge even when it moves around. Combining feature selectivity and invariance is integral to successful object recognition. Considering the marsupial-eutherian divergence 160 million years ago, we explored whether feature selectivity and invariance was similar in marsupials and eutherians. We recovered the spatial filters and non-linear processing characteristics of the receptive fields of neurons in wallaby V1 and compared them with previous results from cat cortex. We stimulated the neurons in V1 with white Gaussian noise and analysed responses using the non-linear input model. Wallabies exhibit the same high percentage of orientation selective neurons as cats. However, in wallabies we observed a notably higher prevalence of neurons with three or more filters compared to cats. We show that having three or more filters substantially increases phase invariance in the V1s of both species, but that wallaby V1 accentuates this feature, suggesting that the species condenses more processing into the earliest cortical stage. These findings suggest that evolution has led to more than one solution to the problem of creating complex visual processing strategies. KEY POINTS: Previous studies have shown that the primary visual cortex (V1) in mammals is essential for processing complex visual stimuli, with neurons displaying selectivity for edge orientation and position. This research explores whether the visual processing mechanisms in marsupials, such as wallabies, are similar to those in eutherian mammals (e.g. cats). The study found that wallabies have a higher prevalence of neurons with multiple spatial filters in V1, indicating more complex visual processing. Using a non-linear input model, we demonstrated that neurons with three or more filters increase phase invariance. These findings suggest that marsupials and eutherian mammals have evolved similar strategies for visual processing, but marsupials have condensed more capacity to build phase invariance into the first step in the cortical pathway.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to a Letter to the Editor: An alternative mechanism for slow pacemaking.","authors":"Bruce P Bean","doi":"10.1113/JP287843","DOIUrl":"https://doi.org/10.1113/JP287843","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The background sodium leak channel NALCN is a major controlling factor in pituitary cell excitability.","authors":"Marziyeh Belal, Mariusz Mucha, Arnaud Monteil, Paul G Winyard, Robert Pawlak, Jamie J Walker, Joel Tabak, Mino D C Belle","doi":"10.1113/JP284036","DOIUrl":"https://doi.org/10.1113/JP284036","url":null,"abstract":"<p><p>The pituitary gland produces and secretes a variety of hormones that are essential to life, such as for the regulation of growth and development, metabolism, reproduction, and the stress response. This is achieved through an intricate signalling interplay between the brain and peripheral feedback signals that shape pituitary cell excitability by regulating the ion channel properties of these cells. In addition, endocrine anterior pituitary cells spontaneously fire action potentials to regulate the intracellular calcium ([Ca²⁺]_i) level, an essential signalling conduit for hormonal secretion. To this end, pituitary cells must regulate their resting membrane potential (RMP) close to the firing threshold, but the molecular identity of the ionic mechanisms responsible for this remains largely unknown. Here, we revealed that the sodium leak channel NALCN, known to modulate neuronal excitability elsewhere in the brain, regulates excitability in the mouse anterior endocrine pituitary cells. Using viral transduction combined with powerful electrophysiology methods and calcium imaging, we show that NALCN forms the major Na⁺ leak conductance in these cells, appropriately tuning cellular RMP for sustaining spontaneous firing activity. Genetic depletion of NALCN channel activity drastically hyperpolarised these cells, suppressing their firing and [Ca²⁺]_i oscillations. Remarkably, despite this profound function of NALCN conductance in controlling pituitary cell excitability, it represents a very small fraction of the total cell conductance. Because NALCN responds to hypothalamic hormones, our results also provide a plausible mechanism through which hormonal feedback signals from the brain and body could powerfully affect pituitary activity to influence hormonal function. KEY POINTS: Pituitary hormones are essential to life as they regulate important physiological processes, such as growth and development, metabolism, reproduction and the stress response. Pituitary hormonal secretion relies on the spontaneous electrical activity of pituitary cells and co-ordinated inputs from the brain and periphery. This appropriately regulates intracellular calcium signals in pituitary cells to trigger hormonal release. Using viral transduction in combination with electrophysiology and calcium imaging, we show that the activity of the background leak channel NALCN is a major controlling factor in eliciting spontaneous electrical activity and intracellular calcium signalling in pituitary cells. Remarkably, our results revealed that a minute change in NALCN activity could have a major influence on pituitary cell excitability. Our study provides a plausible mechanism through which the brain and body could intricately control pituitary activity to influence hormonal function.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Displacement of extracellular chloride by immobile anionic constituents of the brain's extracellular matrix.","authors":"Kieran P Normoyle, Kyle P Lillis, Kiyoshi Egawa, Melanie A McNally, Mousumi Paulchakrabarti, Biswa P Coudhury, Lauren Lau, Fu Hung Shiu, Kevin J Staley","doi":"10.1113/JP285463","DOIUrl":"https://doi.org/10.1113/JP285463","url":null,"abstract":"<p><p>GABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABA_A receptor activation have uniquely small driving forces: their reversal potential (E_GABA) is very close to the resting membrane potential. As a consequence, GABA_A currents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl). Local cytoplasmic Cl concentrations vary widely because of displacement of mobile Cl ions by relatively immobile anions. Here, we use new reporters of extracellular chloride (Cl^- _o) to demonstrate that Cl is displaced in the extracellular space by high and spatially heterogenous concentrations of immobile anions including sulfated glycosaminoglycans (sGAGs). Cl^- _o varies widely, and the mean Cl^- _o is only half the canonical concentration (i.e. the Cl concentration in the cerebrospinal fluid). These unexpectedly low and heterogenous Cl^- _o domains provide a mechanism to link the varied but highly stable distribution of sGAGs and other immobile anions in the brain's extracellular space to neuronal signal processing via the effects on the amplitude and direction of GABA_A transmembrane Cl currents. KEY POINTS: Extracellular chloride concentrations in the brain were measured using a new chloride-sensitive organic fluorophore and two-photon fluorescence lifetime imaging. In vivo, the extracellular chloride concentration was spatially heterogenous and only half of the cerebrospinal fluid chloride concentration Stable displacement of extracellular chloride by immobile extracellular anions was responsible for the low extracellular chloride concentration The changes in extracellular chloride were of sufficient magnitude to alter the conductance and reversal potential of GABA_A chloride currents The stability of the extracellular matrix, the impact of the component immobile anions, including sulfated glycosaminoglycans on extracellular chloride concentrations, and the consequent effect on GABA_A signalling suggests a previously unappreciated mechanism for modulating GABA_A signalling.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author response to Panza et al.","authors":"Alysha T Bogard, Andrew Q Tan","doi":"10.1113/JP287844","DOIUrl":"https://doi.org/10.1113/JP287844","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to - Exposing mice to extremely hypertonic treatments: A recurring problem in lactate research.","authors":"Seth F McCarthy, Isabel Moberg, Sarah Bellaflor, Michael S Finch, Tom J Hazell, Rebecca E K MacPherson","doi":"10.1113/JP287909","DOIUrl":"https://doi.org/10.1113/JP287909","url":null,"abstract":"","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}