Transduction Of Stimuli Research Articles

Molecular taxonomy of nociceptors and pruriceptors.

Molecular taxonomy of nociceptors and pruriceptors.

Dermal Sensory Regenerative Peripheral Nerve Interface for Reestablishing Sensory Nerve Feedback in Peripheral Afferents in the Rat.

Without meaningful, intuitive sensory feedback, even the most advanced myoelectric devices require significant cognitive demand to control. The dermal sensory regenerative peripheral nerve interface (DS-RPNI) is a biological interface designed to establish high-fidelity sensory feedback from prosthetic limbs. DS-RPNIs were constructed in rats by securing fascicles of residual sensory peripheral nerves into autologous dermal grafts, with the objectives of confirming regeneration of sensory afferents within DS-RPNIs and establishing the reliability of afferent neural response generation with either mechanical or electrical stimulation. Two months after implantation, DS-RPNIs were healthy and displayed well-vascularized dermis with organized axonal collaterals throughout and no evidence of neuroma. Electrophysiologic signals were recorded proximal from DS-RPNI's sural nerve in response to both mechanical and electrical stimuli and compared with (1) full-thickness skin, (2) deepithelialized skin, and (3) transected sural nerves without DS-RPNI. Mechanical indentation of DS-RPNIs evoked compound sensory nerve action potentials (CSNAPs) that were like those evoked during indentation of full-thickness skin. CSNAP firing rates and waveform amplitudes increased in a graded fashion with increased mechanical indentation. Electrical stimuli delivered to DS-RPNIs reliably elicited CSNAPs at low current thresholds, and CSNAPs gradually increased in amplitude with increasing stimulation current. These findings suggest that afferent nerve fibers successfully reinnervate DS-RPNIs, and that graded stimuli applied to DS-RPNIs produce proximal sensory afferent responses similar to those evoked from normal skin. This confirmation of graded afferent signal transduction through DS-RPNI neural interfaces validate DS-RPNI's potential role of facilitating sensation in human-machine interfacing. The DS-RPNI is a novel biotic-abiotic neural interface that allows for transduction of sensory stimuli into neural signals. It is expected to advance the restoration of natural sensation and development of sensorimotor control in prosthetics.

The enteric nervous system.

Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.

Whole exome sequencing of 28 families of Danish descent reveals novel candidate genes and pathways in developmental dysplasia of the hip

Developmental dysplasia of the hip (DDH) is a common condition involving instability of the hip with multifactorial etiology. Early diagnosis and treatment are critical as undetected DDH is an important cause of long-term hip complications. Better diagnostics may be achieved through genetic methods, especially for patients with positive family history. Several candidate genes have been reported but the exact molecular etiology of the disease is yet unknown. In the present study, we performed whole exome sequencing of DDH patients from 28 families with at least two affected first-degree relatives. Four genes previously not associated with DDH (METTL21B, DIS3L2, PPP6R2, and TM4SF19) were identified with the same variants shared among affected family members, in more than two families. Among known association genes, we found damaging variants in DACH1, MYH10, NOTCH2, TBX4, EVC2, OTOG, and SHC3. Mutational burden analysis across the families identified 322 candidate genes, and enriched pathways include the extracellular matrix, cytoskeleton, ion-binding, and detection of mechanical stimulus. Taken altogether, our data suggest a polygenic mode of inheritance for DDH, and we propose that an impaired transduction of the mechanical stimulus is involved in the etiopathological mechanism. Our findings refine our current understanding of candidate causal genes in DDH, and provide a foundation for downstream functional studies.

A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins

Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion channels. Mechanisms regulating trafficking and localization of these proteins in the dendrite are unknown. By lectin/immunofluorescence staining and in vivo correlative light-electron microscopy (CLEM), we identify a retinitis pigmentosa-2 (RP2), ESCRT-0 and synaptophysin-containing multivesicular organelle that is not part of generic recycling/degradative/exosome pathways. The organelle’s intraluminal vesicles contain the olfactory transduction proteins except for Golf subunits Gγ13 and Gβ1. Instead, Gβ1 colocalizes with RP2 on the organelle’s outer membrane. The organelle accumulates in response to stimulus deprivation, while odor stimuli or adenylate cyclase activation cause outer membrane disintegration, release of intraluminal vesicles, and RP2/Gβ1 translocation to the base of olfactory cilia. Together, these findings reveal the existence of a dendritic organelle that mediates both stimulus-regulated storage of olfactory ciliary transduction proteins and membrane-delimited sorting important for G protein heterotrimerization.

Neuroimmune crosstalk in the skin: a delicate balance governing inflammatory processes.

With its unique structure and large numbers of immune cells, the skin is one of the body's first lines of defense against attacks from the environment. It is also innervated by a dense meshwork of primary sensory neurons, including nociceptive fibers specializing in the detection and transduction of harmful stimuli that can elicit pain. This tissue is, therefore, a key organ for studies of neuroimmune interactions and their impact on the host response to environmental challenges. Neuroimmune crosstalk in the skin is crucial for the regulation of inflammation, tissue repair, and host defense against pathogens. A better understanding of this regulation would facilitate the identification of new molecular targets for the treatment of skin diseases.

Functional analysis of mitogen-activated protein kinases (MAPKs) in potato under biotic and abiotic stress.

Biotic and abiotic stresses are the main constrain of potato (Solanum tuberosum L.) production all over the world. To overcome these hurdles, many techniques and mechanisms have been used for increasing food demand for increasing population. One of such mechanism is mitogen-activated protein kinase (MAPK) cascade, which is significance regulators of MAPK pathway under various biotic and abiotic stress conditions in plants. However, the acute role in potato for various biotic and abiotic resistance is not fully understood. In eukaryotes including plants, MAPK transfer information from sensors to responses. In potato, biotic and abiotic stresses, as well as a range of developmental responses including differentiation, proliferation, and cell death in plants, MAPK plays an essential role in transduction of diverse extracellular stimuli. Different biotic and abiotic stress stimuli such as pathogen (bacteria, virus, and fungi, etc.) infections, drought, high and low temperatures, high salinity, and high or low osmolarity are induced by several MAPK cascade and MAPK gene families in potato crop. The MAPK cascade is synchronized by numerous mechanisms, including not only transcriptional regulation but also through posttranscriptional regulation such as protein-protein interactions. In this review, we will discuss the recent detailed functional analysis of certain specific MAPK gene families which are involved in resistance to various biotic and abiotic stresses in potato. This study will also provide new insights into functional analysis of various MAPK gene families in biotic and abiotic stress response as well as its possible mechanism.

Transient Receptor Potential channels (TRP) in GtoPdb v.2022.1

Transient Receptor Potential channels (TRP) in GtoPdb v.2022.1

Regulation of Aging and Longevity by Ion Channels and Transporters.

Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.

The Pivotal Role of Transient Receptor Potential Channels in Oral Physiology.

Transient Receptor Potential (TRP) Channels constitute a large family of non-selective permeable ion channels involved in the perception of environmental stimuli with a central and continuously expanding role in oral tissue homeostasis. Recent studies indicate the regulatory role of TRPs in pulp physiology, oral mucosa sensation, dental pain nociception and salivary gland secretion. This review provides an update on the diverse functions of TRP channels in the physiology of the oral cavity, with emphasis on their cellular location, the underlying molecular mechanisms and clinical significance. A structured search of bibliographic databases (PubMed and MEDLINE) was performed for peer-reviewed studies on the function of TRP channels on oral cavity physiology in the last ten years. A qualitative content analysis was performed of screened papers and a critical discussion on the main findings is provided. TRPs expression has been detected in major cell types of the oral cavity, including odontoblasts, periodontal ligament, oral epithelial, salivary gland cells, and chondrocytes of temporomandibular joints, where they mediate signal perception and transduction of mechanical, thermal, and osmotic stimuli. They contribute to pulp physiology through dentin formation, mineralization, and periodontal ligament formation, along with alveolar bone remodeling in the dental pulp and periodontal ligament cells. TRPs are also involved in oral mucosa sensation, dental pain nociception, saliva secretion, swallowing reflex and temporomandibular joints' development. Various TRP channels regulate oral cavity homeostasis, playing an important role in the transduction of external stimuli to intracellular signals in a cell typespecific manner and presenting promising drug targets for the development of pharmacological strategies to manage oral diseases.

Light-stimulated dephosphorylation of the BiP-like protein, SmicHSP75 (SBiP1) from Symbiodinium microadriaticum is inhibited by elevated but not low temperature and suggests regulation of the chaperone function.

Specific phosphorylation/dephosphorylation processes are fundamental for the transduction of external stimuli into physiological responses. A few of these processes appear to be modulated by light in cultured Symbiodinium microadriaticum since the BiP-like protein SmicHSP75 undergoes threonine dephosphorylation upon light stimuli. Several isoforms of the protein are encoded in the S. microadriaticum genome and thus, we identified and heterologously expressed a specific sequence corresponding to the previously identified SmicHSP75 isoform to obtain a highly specific antibody. We then determined by western blot analysis, that the detected light-stimulated changes in SmicHSP75 threonine phosphorylation were not due to changes in the protein expression and explored further the effect of lower than normal and higher stressful temperature, on the phosphorylation levels of the protein. Upon long-term (12 h) exposure of the cells to the low temperature of 21ºC under darkness, the protein was found significantly phosphorylated; however, light exposure for 30 min caused a dephosphorylation effect like the 26ºC control treatment. On the other hand, in cells exposed to 32ºC for 12 h under darkness, the highly Thr-phosphorylated SmicHSP75 was converted to a low-level phosphorylated protein. Likewise, short term (30 min) exposure to 32ºC under dark conditions caused dephosphorylation of the protein, similar to what was observed upon long-term exposure to 32ºC and upon light stimulation of cells under the normal temperature of 26ºC. These data suggested activation/inactivation of the chaperone function of SmicHSP75 by regulation of its Thr phosphorylation levels under heat stress conditions in Symbiodinium microadriaticum, independent of changes in protein expression.

Supraspinal Mechanisms Underlying Ocular Pain.

Supraspinal mechanisms of pain are increasingly understood to underlie neuropathic ocular conditions previously thought to be exclusively peripheral in nature. Isolating individual causes of centralized chronic conditions and differentiating them is critical to understanding the mechanisms underlying neuropathic eye pain and ultimately its treatment. Though few functional imaging studies have focused on the eye as an end-organ for the transduction of noxious stimuli, the brain networks related to pain processing have been extensively studied with functional neuroimaging over the past 20 years. This article will review the supraspinal mechanisms that underlie pain as they relate to the eye.

Turning the Curve Into Straight: Phenogenetics of the Spine Morphology and Coordinate Maintenance in the Zebrafish.

The vertebral column, or spine, provides mechanical support and determines body axis posture and motion. The most common malformation altering spine morphology and function is adolescent idiopathic scoliosis (AIS), a three-dimensional spinal deformity that affects approximately 4% of the population worldwide. Due to AIS genetic heterogenicity and the lack of suitable animal models for its study, the etiology of this condition remains unclear, thus limiting treatment options. We here review current advances in zebrafish phenogenetics concerning AIS-like models and highlight the recently discovered biological processes leading to spine malformations. First, we focus on gene functions and phenotypes controlling critical aspects of postembryonic aspects that prime in spine architecture development and straightening. Second, we summarize how primary cilia assembly and biomechanical stimulus transduction, cerebrospinal fluid components and flow driven by motile cilia have been implicated in the pathogenesis of AIS-like phenotypes. Third, we highlight the inflammatory responses associated with scoliosis. We finally discuss recent innovations and methodologies for morphometrically characterize and analyze the zebrafish spine. Ongoing phenotyping projects are expected to identify novel and unprecedented postembryonic gene functions controlling spine morphology and mutant models of AIS. Importantly, imaging and gene editing technologies are allowing deep phenotyping studies in the zebrafish, opening new experimental paradigms in the morphometric and three-dimensional assessment of spinal malformations. In the future, fully elucidating the phenogenetic underpinnings of AIS etiology in zebrafish and humans will undoubtedly lead to innovative pharmacological treatments against spinal deformities.

TRP Channels as Molecular Targets to Relieve Cancer Pain.

Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.

Combining Topical Agonists With the Recording of Event-Related Brain Potentials to Probe the Functional Involvement of TRPM8, TRPA1 and TRPV1 in Heat and Cold Transduction in the Human Skin

TRP channels play a central role in the transduction of thermal and nociceptive stimuli by free nerve endings. Most of the research on these channels has been conducted in vitro or in vivo in nonhuman animals and translation of these results to humans must account for potential experimental biases and interspecific differences. This study aimed at evaluating the involvement of TRPM8, TRPA1 and TRPV1 channels in the transduction of heat and cold stimuli by the human thermonociceptive system. For this purpose, we evaluated the effects of topical agonists of these 3 channels (menthol, cinnamaldehyde and capsaicin) on the event-related brain potentials (ERPs) elicited by phasic thermal stimuli (target temperatures: 10°C, 42°C, and 60°C) selected to activate cold Aδ thermoreceptors, warm sensitive C thermoreceptors and heat sensitive Aδ polymodal nociceptors. Sixty-four participants were recruited, 16 allocated to each agonist solution group (20% menthol, 10% cinnamaldehyde, .025% capsaicin and 1% capsaicin). Participants were treated sequentially with the active solution on one forearm and vehicle only on the other forearm for 20 minutes. Menthol decreased the amplitude and increased the latency of cold and heat ERPs. Cinnamic aldehyde decreased the amplitude and increased the latency of heat but not cold ERPs. Capsaicin decreased the amplitude and increased the latency of heat ERPs and decreased the amplitude of the N2P2 complex of the cold ERPs without affecting the earlier N1 wave or the latencies of the peaks. These findings are compatible with previous evidence indicating that TRPM8 is involved in innocuous cold transduction and that TRPV1 and TRPA1 are involved in noxious heat transduction in humans. PerspectiveBy chemically modulating TRPM8, TRPA1 and TRPV1 reactivity (key molecules in the transduction of temperature) and assessing how this affected EEG responses to the activation of cold thermoreceptors and heat nociceptors, we aimed at confirming the role of these channels in a functional healthy human model.

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

BackgroundSensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated.MethodsWe performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4.ResultsAll proteins were found to be expressed in human cochlear structures. Our findings illustrate cochlear structures that mediate mechano-electric transduction of auditory stimuli, neuronal conductance, and neuronal plasticity to be involved in age-related hearing loss.ConclusionsOur results suggest common genetic variation to influence structural resilience to damage as well as cochlear recovery after trauma, which protect against accumulated damage to cochlear structures and the development of hearing loss over time.

The antennal scape organ of Scutigera coleoptrata (Myriapoda) and a new type of arthropod tip-pore sensilla integrating scolopidial components

BackgroundCentipedes are terrestrial, predatory arthropods with specialized sensory organs. However, many aspects of their sensory biology are still unknown. This also concerns hygroreception, which is especially important for centipedes, as their epicuticle is thin and they lose water rapidly at low humidity. Thus, the detection of humid places is vital but to date no definite hygroreceptor was found in centipedes. House centipedes (Scutigeromorpha) possess a peculiar opening at the base of their antenna, termed ‘scape organ’, that houses up to 15 cone-shaped sensilla in a cavity. Lacking wall and tip-pores, these socket-less sensilla may be hypothesized to function as hygroreceptors similar to those found in hexapods.ResultsThe cone-shaped sensilla in the scape organ as well as nearby peg-shaped sensilla are composed of three biciliated receptor cells and three sheath cells. A tip-pore is present but plugged by a highly electron-dense secretion, which also overlays the entire inner surface of the cavity. Several solitary recto-canal epidermal glands produce the secretion. Receptor cell type 1 (two cells in cone-shaped sensilla, one cell in peg-shaped sensilla) possesses two long dendritic outer segments that project to the terminal pore. Receptor cell type 2 (one cell in both sensilla) possesses two shorter dendritic outer segments connected to the first (proximal) sheath cell that establishes a scolopale-like structure, documented for the first time in detail in a myriapod sensillum.ConclusionsThe nearly identical configuration of receptor cells 1 with their long dendritic outer segments in both sensilla is similar to hexapod hygroreceptors. In Scutigera coleoptrata, however, the mechanism of stimulus transduction is different. Water vapor may lead to swelling and subsequent elongation of the plug pin that enters the terminal pore, thus causing stimulation of the elongated dendritic outer segments. The interconnection of receptor cell 2 with short outer dendritic segments to a scolopale-like structure potentially suits both sensilla for vibration or strain detection. Thus, both sensilla located at the antennal base of scutigeromorph centipedes fulfill a dual function.

A small molecule screen identifies novel inhibitors of mechanosensory nematocyst discharge in Hydra

Cnidarians are characterized by the possession of stinging organelles, called nematocysts, which they use for prey capture and defense. Nematocyst discharge is controlled by a mechanosensory apparatus with analogies to vertebrate hair cells. Members of the transient receptor potential (TRPN) ion channel family are supposed to be involved in the transduction of the mechanical stimulus. A small molecule screen was performed to identify compounds that affect nematocyst discharge in Hydra. We identified several [2.2]paracyclophanes that cause inhibition of nematocyst discharge in the low micro-molar range. Further structure–activity analyses within the compound class of [2.2]paracyclophanes showed common features that are required for the inhibitory activity of the [2.2]paracyclophane core motif. This study demonstrates that Hydra can serve as a model for small molecule screens targeting the mechanosensory apparatus in native tissues.

Molecular markers associated with the outcome of tamoxifen treatment in estrogen receptor-positive breast cancer patients: scoping review and in silico analysis

Tamoxifen (TMX) is used as adjuvant therapy for estrogen receptor-positive (ER+) breast cancer cases due to its affinity and inhibitory effects. However, about 30% of cases show drug resistance, resulting in recurrence and metastasis, the leading causes of death. A literature review can help to elucidate the main cellular processes involved in TMX resistance. A scoping review was performed to find clinical studies investigating the association of expression of molecular markers profiles with long-term outcomes in ER+ patients treated with TMX. In silico analysis was performed to assess the interrelationship among the selected markers, evaluating the joint involvement with the biological processes. Forty-five studies were selected according to the inclusion and exclusion criteria. After clustering and gene ontology analysis, 23 molecular markers were significantly associated, forming three clusters of strong correlation with cell cycle regulation, signal transduction of proliferative stimuli, and hormone response involved in morphogenesis and differentiation of mammary gland. Also, it was found that overexpression of markers in selected clusters is a significant indicator of poor overall survival. The proposed review offered a better understanding of independent data from the literature, revealing an integrative network of markers involved in cellular processes that could modulate the response of TMX. Analysis of these mechanisms and their molecular components could improve the effectiveness of TMX.

Transient Receptor Potential channels (TRP) in GtoPdb v.2021.3

Transient Receptor Potential channels (TRP) in GtoPdb v.2021.3