Differential encoding of mammalian proprioception by voltage-gated sodium channels

Science Advances, Год журнала: 2025, Номер 11(2)

Опубликована: Янв. 8, 2025

Animals requiring purposeful movement for survival are endowed with mechanoreceptors, called proprioceptors, that provide essential sensory feedback from muscles and joints to spinal cord circuits, which modulates motor output. Despite the nature of proprioceptive signaling in daily life, mechanisms governing proprioceptor activity poorly understood. Here, we identified nonredundant roles two voltage-gated sodium channels (Na V s), Na 1.1 1.6, mammalian proprioception. Deletion 1.6 somatosensory neurons cKO mice) causes severe deficits accompanied by loss transmission, contrasts our previous findings using similar mouse models target ). In animals, observed impairments end-organ structure a marked reduction skeletal muscle myofiber size were absent mice. We attribute differential contributions distinct cellular localization patterns. Collectively, evidence s uniquely shape neural within modality.

Язык: Английский

---

Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common?

Cells, Год журнала: 2021, Номер 10(8), С. 1867 - 1867

Опубликована: Июль 23, 2021

Post orgasmic illness syndrome is a rare, mysterious condition with an unknown pathomechanism and uncertain treatment. The symptoms of post last about 2-7 days after ejaculation. current hypothesis proposes that the primary injury in acute compression proprioceptive axonopathy muscle spindle, as suspected delayed onset soreness. terminal arbor degeneration-like lesion soreness theorized to be stress response energy-depleted dysfunctional mitochondria-induced impairment Piezo2 channels glutamate vesicular release. recurring each ejaculation are suggested analogous repeated bout effect However, there differences pathomechanism, mostly attributed extent secondary tissue damage spermidine depletion. depletion-induced follows: modulation response, flu-like symptoms, opioid-like withdrawal enhanced deregulation autonomic nervous system. longitudinal dimension soreness, form effect, have cognitive memory consequences, since learning memory-related.

Язык: Английский

---

Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation

Biomolecules, Год журнала: 2022, Номер 12(9), С. 1207 - 1207

Опубликована: Авг. 31, 2022

Piezo2 transmembrane excitatory mechanosensitive ion channels were identified as the principal mechanotransduction for proprioception. Recently, it was postulated that could be acutely microdamaged on an autologous basis at proprioceptive Type Ia terminals in a cognitive demand-induced acute stress response time window when unaccustomed or strenuous eccentric contractions are executed. One consequence of this proposed transient microinjury VGLUT1/Ia synaptic disconnection motoneurons, we can learn from platinum-analogue chemotherapy. A secondary, harsher injury phase with involvement polymodal Aδ and nociceptive C-fibers follow primary impairment proprioception delayed onset muscle soreness. Repetitive reinjury these form repeated bout effects is to tertiary phase. Notably, use associated motor learning memory. The monosynaptic static firing sensory encoding affected stretch reflex immediate microdamage leading impaired proprioception, exaggerated reduced range motion. These channelopathies afferent constitute critical gateway pathophysiology Correspondingly, fatiguing contraction-based pathological hyperexcitation afferents induces reactive oxygen species production-associated neuroinflammation neuronal activation spinal cord

Язык: Английский

---

NaV1.1 is essential for proprioceptive signaling and motor behaviors

eLife, Год журнала: 2022, Номер 11

Опубликована: Окт. 24, 2022

The voltage-gated sodium channel (Na V ), Na 1.1, is well-studied in the central nervous system; conversely, its contribution to peripheral sensory neuron function more enigmatic. Here, we identify a new role for 1.1 mammalian proprioception. RNAscope analysis and vitro patch-clamp recordings genetically identified mouse proprioceptors show ubiquitous expression significant contributions intrinsic excitability. Notably, genetic deletion of neurons caused profound visible motor coordination deficits conditional knockout mice both sexes, similar Piezo2-knockout animals, suggesting that this major contributor proprioceptive transmission. Ex vivo muscle afferent from found loss leads inconsistent unreliable proprioceptor firing characterized by action potential failures during static stretch; responses dynamic vibrations were unaffected. This suggests while combination Piezo2 other isoforms sufficient elicit activity response transient stimuli, required transmission receptor potentials generated sustained stretch. Impressively, afferents heterozygous animals similarly impaired, also exhibited behavioral deficits. Thus, haploinsufficiency impairs behaviors. Importantly, human patients harboring loss-of-function mutations often present with delays ataxia; therefore, our data suggest dysfunction contributes clinical manifestations neurological disorders which compromised. Collectively, first evidence essential signaling

Язык: Английский

---

Molecular characterization of the intact mouse muscle spindle using a multi-omics approach

eLife, Год журнала: 2023, Номер 12

Опубликована: Фев. 6, 2023

The proprioceptive system is essential for the control of coordinated movement, posture, and skeletal integrity. sense proprioception produced in brain using peripheral sensory input from receptors such as muscle spindle, which detects changes length muscles. Despite its importance, molecular composition spindle largely unknown. In this study, we generated comprehensive transcriptomic proteomic datasets entire isolated murine deep masseter muscle. We then associated differentially expressed genes with various tissues composing bioinformatic analysis. Immunostaining verified these predictions, thus establishing new markers different tissues. Utilizing markers, identified differentiation stages capsule cells undergo during development. Together, findings provide characterization intact well tools to study development function health disease.

Язык: Английский

---

Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2

Open Medicine, Год журнала: 2022, Номер 17(1), С. 397 - 402

Опубликована: Янв. 1, 2022

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, multisystem neurodegenerative disease that causes the death of motoneurons (MNs) progressively and eventually leads to paralysis. In contrast, delayed onset muscle soreness (DOMS) defined as soreness, stiffness, loss force-generating capacity, reduced joint range motion, decreased proprioceptive function. Sensory deficits impaired proprioception are common symptoms both ALS DOMS, impairment at sensory terminals in spindle theorized occur both. The important clinical distinction extraocular muscles (EOM) relatively spared ALS, contrast limb skeletal muscles; however, blink reflex goes through gradual later stage progression. Noteworthy is, that, stretch EOM induces reflex. current authors suggest nerve spindles partially responsible for lower reflex, beyond central origin, implies critical role Piezo2 ion channels Wnt-PIP2 signaling this pathomechanism. proposed microinjury on could provide an explanation painless dying-back noncontact injury mechanism theory ALS.

Язык: Английский

---

The atypical ‘hippocampal’ glutamate receptor coupled to phospholipase D that controls stretch‐sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2

Experimental Physiology, Год журнала: 2023, Номер 109(1), С. 81 - 99

Опубликована: Сен. 1, 2023

Abstract A metabotropic glutamate receptor coupled to phospholipase D (PLD‐mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage PLD activation are well established indicate it is a highly atypical receptor. with same present spindle primary sensory terminals where its blockade can totally abolish, double, normal stretch‐evoked firing. We report here first identification of this PLD‐mGluR protein, by capitalizing on expression mechanosensory terminals, developing an enriched source, pharmacological profiling identify optimal ligand, then functionalizing as molecular tool. Evidence from immunofluorescence, western far‐western blotting indicates homomeric GluK2, since GluK2 only protein/receptor subunit terminals. also found lanceolate palisade ending hair follicle, known contain PLD‐mGluR. Finally, mouse model ionotropic function ablated subunit, glutamatergic responses were still present, confirming acts purely metabotropically. conclude kainate signalling metabotropically common other, perhaps all, endings.

Язык: Английский

---

Likely Pathogenic Variants of Cav1.3 and Nav1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways

Biomedicines, Год журнала: 2023, Номер 11(3), С. 933 - 933

Опубликована: Март 17, 2023

Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only the clinical picture ALS heterogenous, but also pain sensation due different types involvement. used be considered painless disease, research has been emerging and depicting more complex representation in ALS. Pain detected even couple years before symptomatic stage ALS, referring primary muscle denervation, although secondary nociceptive causes part picture. A new non-contact dying-back injury mechanism theory recently postulated that irreversible intrafusal proprioceptive Piezo2 microinjury could damage, underlying genetic environmental risk factors. Moreover, this damage proposed dysregulate pathways spinal dorsal horn lost imbalanced subthreshold Ca2+ currents, NMDA activation L-type wide dynamic range neurons. Our investigation first show likely pathogenic variants Cav1.3 encoding CACNA1D gene may play role pathology dysregulation or sensation. Furthermore, our reanalysis shows SCN1A might contribute dysregulated Finally, absence points toward However, molecular investigations are needed identify functionally diverse features novel critical pathway.

Язык: Английский

---

Likely pathogenic variants of SDC3, KCNA2, KCNK1, KCNK16 and HSF1 are in support of acquired irreversible PIEZO2 channelopathy in ALS onset

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Amyotrophic lateral sclerosis is a multisystem progressive neurodegenerative disease. A recent theory of ALS proposed that the disease initiating primary damage an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. Underpinning this these ion channels initiate ultrafast proton-based oscillatory signaling to motor neurons through VGLUT1 hippocampus VGLUT2. This may gradually degenerate in which process K_v1.2 are depleted. Furthermore, it also depletes heat shock transcription factor-1 hippocampus, hence negatively affecting adult hippocampal neurogenesis. In addition, not only PIEZO2-PIEZO2 crosstalk fully disrupted progressively between afferent terminals due lost initiated cross-coupled Huygens synchronization, but PIEZO2-PIEZO1 on periphery. Syndecans, especially syndecan-3 nervous system, critical players maintenance PIEZO crosstalk. The detected charge altering variants likely promotes impairment crosstalk, loss as well. Variants KCNA2 facilitate faster function when prevails, mention potassium current rectifying encoding KCNK1 KCNK16 propel provide autoimmune-like pathogenic background. Moreover, diminishing presence identified HSF1 variants, leading impaired

Язык: Английский

---

One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes

Diabetes, Год журнала: 2024, Номер 73(12), С. 1967 - 1975

Опубликована: Окт. 14, 2024

There are key differences between the central nervous system (CNS) (brain and spinal cord) peripheral (PNS), such as glial cell types, whether there is protection by blood-brain barrier, modes of synaptic connections, etc. However, many more similarities these two arms system, including neuronal structure function, neuroimmune neurovascular interactions, and, perhaps most essentially, balance neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) neurodegeneration (neuronal death, neuropathies axonopathy demyelination). This article brings together current research evidence on shared mechanisms health disease CNS PNS, particularly with metabolic diseases obesity diabetes. supports claim that critically linked previously understudied conditions or may actually be manifesting across entire at same time, through genetic cellular mechanisms. topic has been underexplored due to silos studies brain nerves an overemphasis in neuroscience a field study. likely for how neurons stay healthy versus undergo damage among this one body—providing new opportunities understanding neurological etiology future development neuroprotective therapeutics. Article Highlights

Язык: Английский

---