Role Of Adenosine Triphosphate Research Articles

ATP Acts as a Hydrotrope to Regulate the Phase Separation of NBDY Clusters.

Nonannotated P-body dissociating polypeptide (NBDY) is a recently discovered human microprotein that has been found to be a novel component of the mRNA decapping complex. Previous studies have shown that the phosphorylation of NBDY promotes the liquid phase of the NBDY remixing in vitro. Typically, during the process of phosphorylation, a phosphate group is added to the protein through adenosine triphosphate (ATP) hydrolysis. It has been shown that ATP acts as a biological hydrotrope, affecting the phase separation of proteins in solution. In this study, we utilized simulation methods to investigate the dynamic properties of the NBDY clusters at various ATP concentrations. Our findings demonstrate that ATP can regulate the phase separation of NBDY clusters. Specifically, we identified a critical point in the concentration ratio between ATP and NBDY that exhibits a dual effect on the phase separation of NBDY. We observed that the nonsaturated ATP concentration can facilitate the formation of phase separation, while oversaturated ATP concentration promotes the diffusion of NBDY, and the oversaturated ATP-NBDY interaction impedes the phase separation of NBDY. Additionally, we found that ATPs can bind to the protein surface by aggregating into ATP clusters, which further hinders the diffusion of NBDY clusters. Our work provides general insight into the role of ATP in the phase separation of protein condensates.

Serum, interstitialand sweat ATP in humans exposed to heat stress: Insights into roles of ATP in the heat loss responses.

Hyperthermia increases intravascular adenosine triphosphate (ATP) and is associated with greater hyperthermia-induced cutaneous vasodilation. Hyperthermia may also increase skin interstitial fluid ATP thereby activating cutaneous vascular smooth muscle cells and sweat glands. We evaluated the hypothesis that whole-body heating would increase skin interstitial fluid ATP, and this response would be associated with an increase in cutaneous vasodilation and sweating. Nineteen (8 females) young adults underwent whole-body heating using a water-perfusion suit to increase core temperature by ~1°C during which time cutaneous vascular conductance (CVC, ratio of laser-Doppler blood flow to mean arterial pressure) and sweat rate (ventilated capsule technique) were measured at four forearm skin sites to minimize between-site variations. Dialysate from the skin sites were collected via intradermal microdialysis. Heating increased serum ATP, CVC, and sweat rate (all p ≤ 0.031). However, heating did not modulate dialysate ATP (median, baseline vs. end-heating: 2.38 vs. 2.70 nmol/ml) (p = 0.068), though the effect size was moderate (Cohen's d = 0.566). While the heating-induced increase in CVC was not correlated with changes in serum ATP (r = 0.439, p = 0.060), we observed a negative correlation (rs = -0.555, p = 0.017) between dialysate ATP and CVC. We did not observe a significant correlation between the heating-induced sweating and serum, dialysate, or sweat ATP (rs = 0.091 to -0.322, all p ≥ 0.222). Altogether, we showed that passive heating increases ATP in blood and possibly skin interstitial fluid, with the latter potentially blunting cutaneous vasodilation. However, ATP does not appear to modulate sweating.

ATP Induces Interleukin-8, Intracellular Calcium Release, and ERK1/2 Phosphorylation in Bovine Endometrial Cells, Partially through P2Y Receptors

The bovine endometrium has an important defensive role in the postpartum period that acts when an inflammatory process associated with tissue damage or infection by bacteria is produced. Endometrial cells release cytokines and chemokines that recruit inflammatory cells, which release danger-associated molecular patterns (DAMPs), such as adenosine triphosphate (ATP), and initiate and regulate the inflammatory response. However, the role of ATP in bovine endometrial cells is unclear. The aim of this study was to determine the effect of ATP on interleukin-8 (IL-8) release, intracellular calcium mobilization, ERK1/2 phosphorylation, and the role of P2Y receptors, in bovine endometrial cells. Bovine endometrial (BEND) cells were incubated with ATP and the IL-8 release was determined by the ELISA assay. ATP of 50 and 100 μM significantly increased IL-8 released in BEND cells (50 μM: 23.16 ± 3.82 pg/mL, p = 0.0018; 100 μM: 30.14 ± 7.43 pg/mL, p = 0.0004). ATP (50 μM) also induced rapid intracellular calcium mobilization in Fura-2AM-loaded BEND cells, as well as ERK1/2 phosphorylation (ratio 1.1 ± 0.04, p = 0.0049). Suramin (50 μM), a pan-antagonist of P2Y receptors, partially reduced the intracellular calcium mobilization, ERK1/2 phosphorylation (ratio 0.83 ± 0.08, p = 0.045), and IL-8 release (9.67 ± 0.02 pg/mL, p = 0.014) induced by ATP. Finally, BEND cells expressed higher mRNA levels of P2Y1 and P2Y2 purinergic subtype receptors, and lower levels of P2Y11 and P2Y12 receptors, as determined by RT-qPCR. In conclusion, these results showed that ATP activates pro-inflammatory responses in BEND cells, which are partially mediated via P2Y receptors, and BEND cells express the mRNA of subtypes of P2Y receptors, which could have a key role in bovine endometrial inflammation.

Gene Editing Technologies Targeting TFAM and Its Relation to Mitochondrial Diseases.

Mitochondria are organelles present in the cytoplasm of eukaryotic cells; they play a key role in adenosine triphosphate (ATP) synthesis and oxidative phosphorylation. Mitochondria have their own DNA, mitochondrial DNA (mtDNA), keeping the function of the mitochondria. Mitochondrial transcription factor A (TFAM) is a member of the HMGB subfamily that binds to mtDNA promoters is and considered essential in mtDNA replication and transcription. More recently, TFAM has been shown to play a central role in the maintenance and regulation of mitochondrial copy number, inflammatory response, expression regulation, and mitochondrial genome activity. Gene editing tools such as the CRISPR-Cas 9 technique, TALENs, and other gene editing tools have been used to investigate the role of TFAM in mitochondrial mechanics and biogenesis as well as its correlation to mitochondrial disorders. Thus this chapter brings a summary of mitochondria function, dysfunction, the importance of TFAM in the maintenance of mitochondria, and state of the art of gene editing tools involving TFAM and mtDNA.

Role of adenosine triphosphate and protein kinase A in the force-frequency relationship in isolated rat cardiomyocytes

The physiological heart rate of rodents is around 4-6 Hz, although a stimulus frequency of 1 Hz is generally used in isolated cardiomyocytes to study changes in the contraction-relaxation cycle in cardiac muscle physiology and pathophysiology. Our study investigated the contraction parameters in isolated cardiomyocytes at 1, 2 and 4 Hz stimulation, and the roles of ATP and protein kinase A (PKA) in the force-frequency relationship in isolated cardiomyocytes. The contraction of the cell and intracellular Ca2+ changes were recorded simultaneously during cell stimulation by applying pulses of 6-8 V amplitude with frequencies of 1, 2 and 4 Hz. The increase in stimulus frequency caused a significant decrease in the percentage of shortening, relaxation times, slowing of the relaxation rate, and a significant increase in diastolic Ca2+ levels, but had no effect on the contraction rate and Ca2+ transients. Administration of ATP and N6-benzoyladenosine-3'-5'-cyclic monophosphate (6-BNZ-cAMP) caused an increase in contraction amplitude and speed which were proportional to the stimulus frequency but had no effect on the relaxation times. The experimental results show that the force-stimulus frequency has a negative correlation in isolated myocytes and that energy metabolism and the ?-adrenergic system may be responsible for this relationship.

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity.

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial targets as major determinants of the cardiotoxic effects triggered by an increasing number of chemotherapeutic agents used for both solid and hematological tumors. Mitochondrial toxicity induced by such anticancer therapeutics is due to different mechanisms, generally altering the mitochondrial respiratory chain, energy production, and mitochondrial dynamics, or inducing mitochondrial oxidative/nitrative stress, eventually culminating in cell death. The present review summarizes key mitochondrial processes mediating the cardiotoxic effects of anti-neoplastic drugs, with a specific focus on anthracyclines (ANTs), receptor tyrosine kinase inhibitors (RTKIs) and proteasome inhibitors (PIs).

Contrary to consensus, oxidation of ethanol by human alcohol dehydrogenase (ADH) 1A is activated by ATP

Presently we report that enzymatic oxidation of ethanol (EtOH) by ADH1A alcohol dehydrogenase is strongly accelerated in presence of adenosine triphosphate (ATP), by up to the factor of 20 in vitro. This result provides a different look on the role of ATP in functioning of alcohol dehydrogenases (ADH), which until presently were a textbook example of enzymes not requiring ATP and successfully operating without it. However, ATP is available in every living cell and will activate reactions conducted by ADH enzymes in vivo. Therefore, the body of published literature describing properties of numerous ADH enzymes requires a thorough revision.

Role of ATP in Extracellular Vesicle Biogenesis and Dynamics.

Adenosine triphosphate (ATP) is among the molecules involved in the immune response. It acts as danger signal that promotes inflammation by activating both P2X and P2Y purinergic receptors expressed in immune cells, including microglia, and tumor cells. One of the most important receptors implicated in ATP-induced inflammation is P2X7 receptor (P2X7R). The stimulation of P2X7R by high concentration of ATP results in cell proliferation, inflammasome activation and shedding of extracellular vesicles (EVs). EVs are membrane structures released by all cells, which contain a selection of donor cell components, including proteins, lipids, RNA and ATP itself, and are able to transfer these molecules to target cells. ATP stimulation not only promotes EV production from microglia but also influences EV composition and signaling to the environment. In the present review, we will discuss the current knowledge on the role of ATP in the biogenesis and dynamics of EVs, which exert important functions in physiology and pathophysiology.

Purinergic Signaling of ATP in COVID-19 Associated Guillain-Barré Syndrome.

Declared as a global public health emergency, coronavirus disease 2019 (COVID-19) is presented as a disease of the respiratory tract, although severe cases can affect the entire organism. Several studies have shown neurological symptoms, ranging from dizziness and loss of consciousness to cerebrovascular and neurodegenerative diseases. In this context, Guillain-Barré syndrome, an immune-mediated inflammatory neuropathy, has been closely associated with critical cases of infection with “severe acute respiratory syndrome of coronavirus 2” (SARS-CoV-2), the etiological agent of COVID-19. Its pathophysiology is related to a generalized inflammation that affects the nervous system, but neurotropism was also revealed by the new coronavirus, which may increase the risk of neurological sequel, as well as the mortality of the disease. Thus, considering the comorbidities that SARS-CoV-2 infection can promote, the modulation of purinergic signaling can be applied as a potential therapy. In this perspective, given the role of adenosine triphosphate (ATP) in neural intercommunication, the P2X7 receptor (P2X7R) acts on microglia cells and its inhibition may be able to reduce the inflammatory condition of neurodegenerative diseases. Finally, alternative measures to circumvent the reality of the COVID-19 pandemic need to be considered, given the severity of critical cases and the viral involvement of multiple organs.Graphical

Glial ATP and Large Pore Channels Modulate Synaptic Strength in Response to Chronic Inactivity

A key feature of neurotransmission is its ability to adapt to changes in neuronal environment, which is essential for many brain functions. Homeostatic synaptic plasticity (HSP) emerges as a compensatory mechanism used by neurons to adjust their excitability in response to changes in synaptic activity. Recently, glial cells emerged as modulators for neurotransmission by releasing gliotransmitters into the synaptic cleft through pathways that include P2X7 receptors (P2X7R), connexons, and pannexons. However, the role of gliotransmission in the activity-dependent adjustment of presynaptic strength is still an open question. Here, we investigated whether glial cells participate in HSP upon chronic inactivity and the role of adenosine triphosphate (ATP), connexin43 hemichannels (Cx43HCs), and pannexin1 (Panx1) channels in this process. We used immunocytochemistry against vesicular glutamate transporter 1 (vGlut1) to estimate changes in synaptic strength in hippocampal dissociated cultures. Pharmacological manipulations indicate that glial-derived ATP and P2X7R are required for HSP. In addition, inhibition of Cx43 and Panx1 channels reveals a pivotal role for these channels in the compensatory adjustment of synaptic strength, emerging as new pathways for ATP release upon inactivity. The involvement of Panx1 channels was confirmed by using Panx1-deficient animals. Lacking Panx1 in neurons is sufficient to prevent the P2X7R-dependent upregulation of presynaptic strength; however, the P2X7R-dependent compensatory adjustment of synapse density requires both neuronal and glial Panx1. Together, our data supports an essential role for glial ATP signaling and Cx43HCs and Panx1 channels in the homeostatic adjustment of synaptic strength in hippocampal cultures upon chronic inactivity.

The role of ATP in cough hypersensitivity syndrome: new targets for treatment.

Clinically, chronic cough can be effectively controlled in most patients by etiological treatment; however, there remain a small number of patients whose cough has unidentifiable etiology or where treatment efficacy is poor following etiology identification, whose condition is described as unexplained chronic cough or refractory chronic cough. Patients with refractory chronic or unexplained chronic cough commonly have increased cough reflex sensitivity, which has been described as cough hypersensitivity syndrome. The adenosine triphosphate (ATP)-gated P2X3 receptor may be a key link in the activation of sensory neurons that regulate cough reflexes and has recently draw attention as a potential target for the treatment of refractory chronic cough, with a number of clinical studies validating the therapeutic effects of P2X3 receptor antagonists in patients with this condition. As the energy source for various cells in vivo, ATP localizes within cells under normal physiological conditions, and has physiological functions, including in metabolism; however, under some pathological circumstances, ATP can act as a neuromodulator and is released into the extracellular space in large quantities as a signal transduction molecule. In addition, ATP is involved in regulation of airway inflammation and the cough reflex. Here, we review the generation, release, and regulation of ATP during airway inflammation and its role in the etiology of cough hypersensitivity syndrome, including the potential underlying mechanism.

Extracellular nucleotide signaling in solid organ transplantation.

The role of extracellular purine nucleotides, including adenosine triphosphate (ATP) and adenosine, as modulators of posttransplantation outcome and ischemia-reperfusion injury is becoming increasingly evident. Upon pathological release of ATP, binding and activation of P2 purinergic surface receptors promote tissue injury and inflammation, while the expression and activation of P1 receptors for adenosine have been shown to attenuate inflammation and limit ischemia-induced damage, which are central to the viability and long-term success of allografts. Here we review the current state of the transplant field with respect to the role of extracellular nucleotide signaling, with a focus on the sources and functions of extracellular ATP. The connection between ischemia reperfusion, purinergic signaling, and graft preservation, as well as the role of ATP and adenosine as driving factors in the promotion and suppression of posttransplant inflammation and allograft rejection, are discussed. We also examine novel therapeutic approaches that take advantage of the ischemia-reperfusion-responsive and immunomodulatory roles for purinergic signaling with the goal of enhancing graft viability, attenuating posttransplant inflammation, and minimizing complications including rejection, graft failure, and associated comorbidities.

ATP Converts Aβ42 Oligomer into Off-Pathway Species by Making Contact with Its Backbone Atoms Using Hydrophobic Adenosine.

Adenosine triphosphate (ATP) is newly expected to be involved in the clearance of amyloid β 1-42 (Aβ42) fibril and its precursors, Aβ42 oligomer. Meanwhile, the microscopic mechanism of the role in dissolving the protein aggregate still remains elusive. Aiming to elucidate the mechanism, we examined effects of ATP on the conformational change and thermodynamic stability of the protomer dimer of Aβ42 pentamer and tetramer, Aβ42(9), by employing all-atom molecular dynamics simulations. We observed interprotomer twisting and intraprotomer peeling of Aβ42(9). These conformational changes remarkably accelerate dissociation of the protomer dimer. However, the presence of ATP itself has no positive effect on dissociation processes of the protomer dimer and a monomer from the dimer, indicating its irrelevance to decomposition of the Aβ42 oligomer. Rather, it could be supposed that ATP prevents additional binding and rebinding of Aβ42 monomers to the Aβ42 oligomer and it then converts Aβ42 oligomer into an off-pathway species which is excluded from Aβ42 fibril growth processes. Interestingly, hydrophobic adenosine in ATP makes contact with Aβ42(9) on its backbone atoms, with respect to both Aβ42 monomers on the edge of Aβ42(9) and dissociated Aβ42 monomers in Aβ42(9). These roles of ATP would be applied without regard to the structural polymorphism of the Aβ42 fibril.

Endogenous genetic risk factor for serious heatstroke: the thermolabile phenotype of carnitine palmitoyltransferase II variant.

AimIn serious heatstroke, elevated body temperature (>40°C) is considered the main cause of illness. Mitochondrial carnitine palmitoyltransferase II (CPT II) plays an important role in adenosine triphosphate (ATP) generation from long‐chain fatty acids, and its thermolabile phenotype of CPT2 polymorphisms leads to ATP production loss under high fever. Whether by heatstroke or influenza, high fever suppresses mitochondrial ATP production in patients with the thermolabile phenotype of CPT2 polymorphisms. We investigated the relation between CPT2 polymorphism and severity of heatstroke with a body temperature of over 40°C.MethodsWe analyzed blood chemistry test results, Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC), Acute Physiologic and Chronic Health Evaluation II, and Sequential Organ Failure Assessment (SOFA) scores, and CPT2 polymorphisms in 24 consecutive patients with severe heatstroke at two university hospitals.ResultsEleven patients carried thermolabile CPT II variants (rs2229291; c.1055T˃G [p.Phe352Cys]) (F352C), and the genotype frequency was greater in heatstroke patients than in healthy volunteers. There was no significant difference in body temperature or blood chemistry data at emergency room arrival between patients with and without the CPT II variants. However, hospital days were longer and initial antithrombin activity was significantly lower in the variant group, suggesting a possible link with early phase vascular endothelial cell dysfunction. The JAAM DIC diagnostic criteria and SOFA scores were also higher in the group. There were no differences in the serum albumin, serum creatine kinase, and fibrin degradation product levels, and platelet counts.ConclusionsIn addition to known risks (e.g., environmental temperature and old age), the CPT II polymorphism [F352C] can be a predisposing genetic risk factor for serious heatstroke with organ disfunction, and lower antithrombin activity.

Effects of adenosine triphosphate concentration on motor force regulation during skeletal muscle contraction

We employ a mechanical model of sarcomere to quantitatively investigate how adenosine triphosphate (ATP) concentration affects motor force regulation during skeletal muscle contraction. Our simulation indicates that there can be negative cross-bridges resisting contraction within the sarcomere and higher ATP concentration would decrease the resistance force from negative cross-bridges by promoting their timely detachment. It is revealed that the motor force is well regulated only when ATP concentration is above a certain level. These predictions may provide insights into the role of ATP in regulating coordination among multiple motors.

Role of ATP as a Key Signaling Molecule Mediating Radiation-Induced Biological Effects.

Adenosine triphosphate (ATP) serves as a signaling molecule for adaptive responses to a variety of cytotoxic agents and plays an important role in mediating the radiation stress-induced responses that serve to mitigate or repair the injurious effects of γ radiation on the body. Indeed, low doses of radiation may have a net beneficial effect by activating a variety of protective mechanisms, including antitumor immune responses. On the other hand, ATP signaling may be involved in the radiation resistance of cancer cells. Here, focusing on our previous work, we review the evidence that low-dose γ irradiation (0.25-0.5 Gy) induces release of extracellular ATP, and that the released ATP mediates multiple radiation-induced responses, including increased intracellular antioxidant synthesis, cell-mediated immune responses, induction of DNA damage repair systems, and differentiation of regulatory T cells.

Functional and therapeutic importance of purinergic signaling in polycystic kidney disease.

Polycystic kidney diseases (PKD) are a group of inherited nephropathies marked with the formation of fluid-filled cysts along the nephron. This renal disorder affects millions of people worldwide, but current treatment strategies are unfortunately limited to supportive therapy, dietary restrictions, and, eventually, renal transplantation. Recent advances in PKD management are aimed at targeting exaggerated cell proliferation and dedifferentiation to interfere with cyst growth. However, not nearly enough is known about the ion transport properties of the cystic cells, or specific signaling pathways modulating channels and transporters in this condition. There is growing evidence that abnormally elevated concentrations of adenosine triphosphate (ATP) in PKD may contribute to cyst enlargement; change in the profile of purinergic receptors may also result in promotion of cystogenesis. The current mini-review is focused on the role of ATP and associated signaling affecting ion transport properties of the renal cystic epithelia.

Mitochondrial respiratory chain defects in autism and other neurodevelopmental disorders

Mitochondrial respiratory electron transport chain (ETC) consists of five multi-subunit enzymes, i.e., complex I-V, which differs not only in structure but also in function, and plays an important role in adenosine triphosphate (ATP) generation by mitochondria. Each of these complexes participates in the generation of proton gradient in the mitochondrial intermembrane space, which is necessary for converting adenosine diphosphate (ADP) into ATP by ATP synthase. Brain has a high demand for energy, and neurons generate energy in the form of ATP through the respiratory chain in the mitochondria. Almost 90% of this energy is provided by mitochondrial ETC. ETC also generates most of the endogenous free radicals, i.e., reactive oxygen species (ROS) of the cell. The normal functions of ETC are essential to maintain physiological function and plasticity of neurons. Therefore, abnormalities in ETC during development, i.e., in utero, infancy and childhood, may be involved in the etiology of neurodevelopmental disorders. The abnormalities in mitochondrial ETC pertaining to neurodevelopmental disorders include mtDNA mutations, altered gene expression, decreased activities and protein expression levels of ETC complexes, and oxidative stress. Here, we review these mitochondrial ETC defects in autism spectrum disorders (ASDs) and other neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder, schizophrenia, Down syndrome and Fragile X syndrome.

Phosphorylation of g-C3N4 for enhanced photocatalytic CO2 reduction

Mesoporous structure of graphitic carbon nitride (g-C3N4) has been proved to be very important for artificial photosynthesis. Phosphate (PO43−) group played an essential role in adenosine triphosphate (ATP) for natural photosynthesis. In this letter, mesoporous phosphorylated g-C3N4 (MPCN) was prepared from bulk g-C3N4 (BCN) by concentrated phosphoric acid post-treatment. Photocatalytic CO2 reduction results revealed that MPCN displayed a much higher activity than BCN. Brunauer-Emmett-Teller (BET) surface areas, time-resolved photoluminescence (PL) spectroscopy, photocurrent and electrochemical impedance (EIS) spectroscopy, and valence band XPS were used to explain the enhanced photocatalytic CO2 conversion performances. It was concluded that the synergistic cooperation of phosphorylation induced mesoporous structure and surface PO43− groups, and the higher photo-induced carrier separation efficiency of MPCN resulted in its enhanced photocatalytic activity for solar-to-fuels conversion over BCN.

Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate

BackgroundSensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored.ObjectiveWe hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung.MethodsWe used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues.ResultsHere we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough.ConclusionThis study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.