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The Journal of General Physiology Sep 2023Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To...
Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work. The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure that the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3-D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.
Topics: Mitochondria; Cytosol; Homeostasis; Membrane Potentials; Adenosine Triphosphate
PubMed: 37615622
DOI: 10.1085/jgp.202213263 -
The Journal of Neuroscience : the... Sep 2023Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials (APs) to...
Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials (APs) to downstream targets. Neuronal polarity is maintained by the axon initial segment (AIS), a region between the soma and axon proper that is also the site of action potential (AP) generation. This polarization between dendrites and axons extends to inhibitory neurotransmission. In adulthood, the neurotransmitter GABA hyperpolarizes dendrites but instead depolarizes axons. These differences in function collide at the AIS. Multiple studies have shown that GABAergic signaling in this region can share properties of either the mature axon or mature dendrite, and that these properties evolve over a protracted period encompassing periadolescent development. Here, we explored how developmental changes in GABAergic signaling affect AP initiation. We show that GABA at the axon initial segment inhibits action potential initiation in layer (L)2/3 pyramidal neurons in prefrontal cortex from mice of either sex across GABA reversal potentials observed in periadolescence. These actions occur largely through current shunts generated by GABA receptors and changes in voltage-gated channel properties that affected the number of channels that could be recruited for AP electrogenesis. These results suggest that GABAergic neurons targeting the axon initial segment provide an inhibitory "veto" across the range of GABA polarity observed in normal adolescent development, regardless of GABAergic synapse reversal potential. GABA receptors are a major class of neurotransmitter receptors in the brain. Typically, GABA receptors inhibit neurons by allowing influx of negatively charged chloride ions into the cell. However, there are cases where local chloride concentrations promote chloride efflux through GABA receptors. Such conditions exist early in development in neocortical pyramidal cell axon initial segments (AISs), where action potentials (APs) initiate. Here, we examined how chloride efflux in early development interacts with mechanisms that support action potential initiation. We find that this efflux, despite moving membrane potential closer to action potential threshold, is nevertheless inhibitory. Thus, GABA at the axon initial segment is likely to be inhibitory for action potential initiation independent of whether chloride flows out or into neurons via these receptors.
Topics: Animals; Mice; Axon Initial Segment; Action Potentials; Chlorides; GABAergic Neurons; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37596053
DOI: 10.1523/JNEUROSCI.0605-23.2023 -
Journal of Neuroscience Research Nov 2023One group of the K ion channels, the small-conductance Ca -activated potassium channels (K 2.x, also known as SK channels family), is widely expressed in neurons as well... (Review)
Review
One group of the K ion channels, the small-conductance Ca -activated potassium channels (K 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca . According to the phylogenic research done on the K 2.x channels family, there are three channels' subtypes: K 2.1, K 2.2, and K 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The K 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. K 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the K 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express K 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The K 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective K 2.2 modulators are promising potential therapeutics for SCAs.
Topics: Rats; Animals; Potassium Channels; Endothelial Cells; Neurons; Membrane Potentials; Purkinje Cells
PubMed: 37466411
DOI: 10.1002/jnr.25233 -
Mechanisms of Ageing and Development Oct 2023A limited number of studies have shown functional changes in mitochondrial ion channels in aging and senescent cells. We have identified, for the first time,...
A limited number of studies have shown functional changes in mitochondrial ion channels in aging and senescent cells. We have identified, for the first time, mitochondrial large-conductance calcium-regulated potassium channels in human smooth muscle mitochondria. This channel, with a conductance of 273 pS, was regulated by calcium ions and membrane potential. Additionally, it was activated by the potassium channel opener NS11021 and blocked by paxilline. Importantly, we have shown that senescence of these cells induced by hydrogen peroxide treatment leads to the disappearance of potassium channel protein levels and channel activity measured by the single channel patch-clamp technique. Our data suggest that disturbances in the expression of mitochondrial large conductance calcium-regulated potassium channels may be hallmarks of cellular senescence and contribute to the misregulation of mitochondrial function in senescent cells.
Topics: Humans; Calcium; Large-Conductance Calcium-Activated Potassium Channels; Calcium Channels; Muscle, Smooth, Vascular; Potassium; Membrane Potential, Mitochondrial; Mitochondria
PubMed: 37689317
DOI: 10.1016/j.mad.2023.111871 -
Scientific Reports Jun 2024The complex architecture and biochemistry of the inner mitochondrial membrane generate ultra-structures with different phospholipid and protein compositions, shapes,...
The complex architecture and biochemistry of the inner mitochondrial membrane generate ultra-structures with different phospholipid and protein compositions, shapes, characteristics, and functions. The crista junction (CJ) serves as an important barrier separating the cristae (CM) and inner boundary membranes (IBM). Thereby CJ regulates the movement of ions and ensures distinct electrical potentials across the cristae (ΔΨ) and inner boundary (ΔΨ) membranes. We have developed a robust and flexible approach to visualize the CJ permeability with super-resolution microscopy as a readout of local mitochondrial membrane potential (ΔΨ) fluctuations. This method involves analyzing the distribution of TMRM fluorescence intensity in a model that is restricted to the mitochondrial geometry. We show that mitochondrial Ca elevation hyperpolarizes the CM most likely caused by Ca sensitive increase of mitochondrial tricarboxylic acid cycle (TCA) and subsequent oxidative phosphorylation (OXPHOS) activity in the cristae. Dynamic multi-parameter correlation measurements of spatial mitochondrial membrane potential gradients, ATP levels, and mitochondrial morphometrics revealed a CJ-based membrane potential overflow valve mechanism protecting the mitochondrial integrity during excessive cristae hyperpolarization.
Topics: Membrane Potential, Mitochondrial; Adenosine Triphosphate; Animals; Mitochondrial Membranes; Signal Transduction; Oxidative Phosphorylation; Calcium; Mitochondria; Microscopy; Humans
PubMed: 38926476
DOI: 10.1038/s41598-024-65595-z -
International Journal of Molecular... May 2024Some signaling processes mediated by G protein-coupled receptors (GPCRs) are modulated by membrane potential. In recent years, increasing evidence that GPCRs are... (Review)
Review
Some signaling processes mediated by G protein-coupled receptors (GPCRs) are modulated by membrane potential. In recent years, increasing evidence that GPCRs are intrinsically voltage-dependent has accumulated. A recent publication challenged the view that voltage sensors are embedded in muscarinic receptors. Herein, we briefly discuss the evidence that supports the notion that GPCRs themselves are voltage-sensitive proteins and an alternative mechanism that suggests that voltage-gated sodium channels are the voltage-sensing molecules involved in such processes.
Topics: Receptors, G-Protein-Coupled; Humans; Animals; Voltage-Gated Sodium Channels; Signal Transduction; Membrane Potentials
PubMed: 38791333
DOI: 10.3390/ijms25105295 -
Neuron Jul 2023Objects and landmarks are crucial for guiding navigation and must be integrated into the cognitive map of space. Studies of object coding in the hippocampus have...
Objects and landmarks are crucial for guiding navigation and must be integrated into the cognitive map of space. Studies of object coding in the hippocampus have primarily focused on activity of single cells. Here, we record simultaneously from large numbers of hippocampal CA1 neurons to determine how the presence of a salient object in the environment alters single-neuron and neural-population activity of the area. The majority of the cells showed some change in their spatial firing patterns when the object was introduced. At the neural-population level, these changes were systematically organized according to the animal's distance from the object. This organization was widely distributed across the cell sample, suggesting that some features of cognitive maps-including object representation-are best understood as emergent properties of neural populations.
Topics: Animals; Humans; Space Perception; Action Potentials; Hippocampus; Neurons
PubMed: 37148872
DOI: 10.1016/j.neuron.2023.04.008 -
Proceedings of the National Academy of... Apr 2024Biological membrane potentials, or voltages, are a central facet of cellular life. Optical methods to visualize cellular membrane voltages with fluorescent indicators...
Biological membrane potentials, or voltages, are a central facet of cellular life. Optical methods to visualize cellular membrane voltages with fluorescent indicators are an attractive complement to traditional electrode-based approaches, since imaging methods can be high throughput, less invasive, and provide more spatial resolution than electrodes. Recently developed fluorescent indicators for voltage largely report changes in membrane voltage by monitoring voltage-dependent fluctuations in fluorescence intensity. However, it would be useful to be able to not only monitor changes but also measure values of membrane potentials. This study discloses a fluorescent indicator which can address both. We describe the synthesis of a sulfonated tetramethyl carborhodamine fluorophore. When this carborhodamine is conjugated with an electron-rich, methoxy (-OMe) containing phenylenevinylene molecular wire, the resulting molecule, CRhOMe, is a voltage-sensitive fluorophore with red/far-red fluorescence. Using CRhOMe, changes in cellular membrane potential can be read out using fluorescence intensity or lifetime. In fluorescence intensity mode, CRhOMe tracks fast-spiking neuronal action potentials (APs) with greater signal-to-noise than state-of-the-art BeRST 1 (another voltage-sensitive fluorophore). CRhOMe can also measure values of membrane potential. The fluorescence lifetime of CRhOMe follows a single exponential decay, substantially improving the quantification of membrane potential values using fluorescence lifetime imaging microscopy (FLIM). The combination of red-shifted excitation and emission, mono-exponential decay, and high voltage sensitivity enable fast FLIM recording of APs in cardiomyocytes. The ability to both monitor and measure membrane potentials with red light using CRhOMe makes it an important approach for studying biological voltages.
Topics: Membrane Potentials; Fluorescent Dyes; Action Potentials; Cell Membrane; Microscopy, Fluorescence
PubMed: 38551837
DOI: 10.1073/pnas.2315264121 -
Clinical Neurophysiology : Official... Dec 2023Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method...
OBJECTIVE
Utility of the split hand index (SI) in amyotrophic lateral sclerosis (ALS) has been reported when using the compound muscle action potential (CMAP) amplitude method (SI). A motor unit number index (MUNIX) based SI method (SI) was purported to exhibit higher sensitivity. The present study assessed the clinical utility of SI, derived by CMAP amplitude, MUNIX and MScan-MUNE (SI) methods, in ALS.
METHODS
Sixty-two consecutive patients with neuromuscular symptoms (36 ALS and 26 ALS-mimics) were prospectively recruited. The SI was derived by dividing the product of the CMAP amplitude, MUNIX and MScan-MUNE values recorded over first dorsal interosseous and abductor pollicis brevis by values recorded over abductor digit minimi.
RESULTS
SI, SI and SI were significantly reduced in ALS, with SI (area under curve (AUC) = 0.801) and SI (AUC = 0.805) exhibiting greater diagnostic utility than SI (AUC = 0.713). SI and SI exhibited significant correlations with clinical measures of functional disability and weakness of intrinsic hand muscles.
CONCLUSIONS
SI differentiated ALS from mimic disorders, with SI and SI exhibiting greater utility.
SIGNIFICANCE
The split hand index represents could serve as a potential diagnostic biomarker in ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Muscle, Skeletal; Hand; Area Under Curve; Action Potentials; Electromyography
PubMed: 37967511
DOI: 10.1016/j.clinph.2023.09.018