scholarly journals Inbuilt Mechanisms for Overcoming Functional Problems Inherent in Hepatic Microlobular Structure

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Robert D. Cohen ◽  
Christopher L. Brown ◽  
Carole Nickols ◽  
Pauline Levey ◽  
Barbara J. Boucher ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Uncoupling Protein ◽  
Receptor Potential ◽  
Temperature Sensitive ◽  
Blood Flows ◽  
Antibody Staining ◽  
Visual Scoring ◽  
Mammalian Liver ◽  
Transient Receptor ◽  
Healthy Liver

The spherical anatomy of human and rat liver lobules implies that more central cells have less time to carry out their function than more peripherally located cells because blood flows past them more rapidly. This problem could be overcome if more centrilobular cells could operate at higher temperatures than periportal cells. This study presents evidence for such a temperature gradient. Firstly, we use mathematical modelling to demonstrate that temperature increases towards the centre of the lobule. Secondly, we examine the distribution of a heat-generating protein and of a heat-sensitive protein across the rat and human liver lobules. Double-antibody staining of healthy liver from rat and human was used for visual scoring and for automated histomorphometric quantitation of the localisation of uncoupling protein-2 (known to generate heat) and of the transient receptor potential-v4 protein (known as a highly temperature-sensitive membrane protein). Both these proteins were found to be located predominantly in the centrilobular region of liver lobules. These findings support the suggestion that temperature gradients across the liver lobule may have evolved as a solution to the problem of reduced contact time between blood and cells at the centre as compared to the periphery of mammalian liver lobules.

Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system

2007 ◽  
Vol 292 (1) ◽  
pp. R37-R46 ◽  
Author(s):  
Andrej A. Romanovsky
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Open Loop ◽  
Temperature Sensitive ◽  
Functional Architecture ◽  
Set Point ◽  
Sequential Activation ◽  
Thermoregulatory System ◽  
Transient Receptor

While summarizing the current understanding of how body temperature (Tb) is regulated, this review discusses the recent progress in the following areas: central and peripheral thermosensitivity and temperature-activated transient receptor potential (TRP) channels; afferent neuronal pathways from peripheral thermosensors; and efferent thermoeffector pathways. It is proposed that activation of temperature-sensitive TRP channels is a mechanism of peripheral thermosensitivity. Special attention is paid to the functional architecture of the thermoregulatory system. The notion that deep Tb is regulated by a unified system with a single controller is rejected. It is proposed that Tb is regulated by independent thermoeffector loops, each having its own afferent and efferent branches. The activity of each thermoeffector is triggered by a unique combination of shell and core Tbs. Temperature-dependent phase transitions in thermosensory neurons cause sequential activation of all neurons of the corresponding thermoeffector loop and eventually a thermoeffector response. No computation of an integrated Tb or its comparison with an obvious or hidden set point of a unified system is necessary. Coordination between thermoeffectors is achieved through their common controlled variable, Tb. The described model incorporates Kobayashi’s views, but Kobayashi’s proposal to eliminate the term sensor is rejected. A case against the term set point is also made. Because this term is historically associated with a unified control system, it is more misleading than informative. The term balance point is proposed to designate the regulated level of Tb and to attract attention to the multiple feedback, feedforward, and open-loop components that contribute to thermal balance.

Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors

2006 ◽  
Vol 291 (3) ◽  
pp. R541-R550 ◽  
Author(s):  
Dan Ni ◽  
Qihai Gu ◽  
Hong-Zhen Hu ◽  
Na Gao ◽  
Michael X. Zhu ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Thermal Sensitivity ◽  
Receptor Potential ◽  
Ruthenium Red ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Inward Current ◽  
Transient Receptor ◽  
Increasing Temperature

A recent study has demonstrated that increasing the intrathoracic temperature from 36°C to 41°C induced a distinct stimulatory and sensitizing effect on vagal pulmonary C-fiber afferents in anesthetized rats ( J Physiol 565: 295–308, 2005). We postulated that these responses are mediated through a direct activation of the temperature-sensitive transient receptor potential vanilloid (TRPV) receptors by hyperthermia. To test this hypothesis, we studied the effect of increasing temperature on pulmonary sensory neurons that were isolated from adult rat nodose/jugular ganglion and identified by retrograde labeling, using the whole cell perforated patch-clamping technique. Our results showed that increasing temperature from 23°C (or 35°C) to 41°C in a ramp pattern evoked an inward current, which began to emerge after exceeding a threshold of ∼34.4°C and then increased sharply in amplitude as the temperature was further increased, reaching a peak current of 173 ± 27 pA ( n = 75) at 41°C. The temperature coefficient, Q10, was 29.5 ± 6.4 over the range of 35–41°C. The peak inward current was only partially blocked by pretreatment with capsazepine (Δ I = 48.1 ± 4.7%, n = 11) or AMG 9810 (Δ I = 59.2 ± 7.8%, n = 8), selective antagonists of the TRPV1 channel, but almost completely abolished (Δ I = 96.3 ± 2.3%) by ruthenium red, an effective blocker of TRPV1–4 channels. Furthermore, positive expressions of TRPV1–4 transcripts and proteins in these neurons were demonstrated by RT-PCR and immunohistochemistry experiments, respectively. On the basis of these results, we conclude that increasing temperature within the normal physiological range can exert a direct stimulatory effect on pulmonary sensory neurons, and this effect is mediated through the activation of TRPV1, as well as other subtypes of TRPV channels.

scholarly journals Regulatory switch at the cytoplasmic interface controls TRPV channel gating

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lejla Zubcevic ◽  
William F Borschel ◽  
Allen L Hsu ◽  
Mario J Borgnia ◽  
Seok-Yong Lee
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Temperature Sensitive ◽  
Physiological Processes ◽  
Physiological Properties ◽  
Electrophysiological Studies ◽  
Transient Receptor ◽  
Large Rearrangements

Temperature-sensitive transient receptor potential vanilloid (thermoTRPV) channels are activated by ligands and heat, and are involved in various physiological processes. ThermoTRPV channels possess a large cytoplasmic ring consisting of N-terminal ankyrin repeat domains (ARD) and C-terminal domains (CTD). The cytoplasmic inter-protomer interface is unique and consists of a CTD coiled around a β-sheet which makes contacts with the neighboring ARD. Despite much existing evidence that the cytoplasmic ring is important for thermoTRPV function, the mechanism by which this unique structure is involved in thermoTRPV gating has not been clear. Here, we present cryo-EM and electrophysiological studies which demonstrate that TRPV3 gating involves large rearrangements at the cytoplasmic inter-protomer interface and that this motion triggers coupling between cytoplasmic and transmembrane domains, priming the channel for opening. Furthermore, our studies unveil the role of this interface in the distinct biophysical and physiological properties of individual thermoTRPV subtypes.

scholarly journals Sperm specific expression of temperature-sensitive ion channel TRPM8 correlates with vertebrate evolution

2014 ◽  
Author(s):  
Rakesh Kumar Majhi ◽  
Somdatta Saha ◽  
Ashutosh Kumar ◽  
Nirlipta Swain ◽  
Luna Goswami ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Vertebrate Evolution ◽  
Temperature Sensitive ◽  
Missense Mutations ◽  
Specific Expression ◽  
Human Genomes ◽  
Trpm8 Gene ◽  
Transient Receptor

Transient Receptor Potential subfamily Melastatin member 8 (TRPM8) is involved in detection of cold temperature and different noxious compounds, execute thermo- as well as chemo-sensitive responses at cellular levels. Here we explored the molecular evolution of TRPM8 by analyzing sequences from different species. We elucidate that different regions of TRPM8 had different levels of selection pressure and the 4-5th transmembrane regions remain highly conserved. Synteny analysis suggests that since vertebrate origin, TRPM8 gene is linked with SPP2, a bone morphogen. We found 16656 TRPM8 variants in 1092 human genomes with top variations are SNPs, insertions and deletions. 692 missense mutations are also mapped to human TRPM8 protein. TRPM8 expresses endogenously in sperm cells of different vertebrates ranging from fish to human. We conclude that TRPM8 has emerged during vertebrate evolution (ca 450 MYA) and sperm-specific expression has guided its molecular evolution. These understandings may have medical importance as well.

scholarly journals MLR-1023 Treatment in Mice and Humans Induces a Thermogenic Program, and Menthol Potentiates the Effect

2021 ◽  
Vol 14 (11) ◽  
pp. 1196
Author(s):  
Candida J. Rebello ◽  
Ann A. Coulter ◽  
Andrew G. Reaume ◽  
Weina Cong ◽  
Luke A. Cusimano ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Blood Glucose ◽  
Transient Receptor Potential ◽  
Glucose Transporter ◽  
Uncoupling Protein ◽  
Fasting Blood Glucose ◽  
Receptor Potential ◽  
Human Adipocytes ◽  
Insulin Sensitizer ◽  
Transient Receptor

A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1β), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial.

scholarly journals TRP Channels in Dental Pain

2013 ◽  
Vol 6 (1) ◽  
pp. 31-36 ◽  
Author(s):  
Gehoon Chung ◽  
Seog Bae Oh
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Functional Expression ◽  
Dental Pain ◽  
Hydrodynamic Theory ◽  
Dentin Hypersensitivity ◽  
Temperature Sensitive ◽  
Dentinal Tubule ◽  
Transient Receptor

Despite the high incidence of dental pain, the mechanism underlying its generation is mostly unknown. Functional expression of temperature-sensitive transient receptor potential (thermo-TRP) channels, such as TRPV1, TRPV2, TRPM8, and TRPA1 in dental primary afferent neurons and TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 in odontoblasts, has been demonstrated and suggested as responsible for dental pain elicited by hot and cold food. However, dental pain induced by light touch or sweet substance cannot be explained by the role of thermo-TRP channels. Most of current therapeutics of dentin hypersensitivity is based on hydrodynamic theory, which argues that light stimuli such as air puff and temperature changes cause fluid movement within dentinal tubule, which is then transduced as pain. To test this theory, various TRP channels as candidates of cellular mechanotransducers were studied for expression in dental primary afferents and odontoblasts. The expression of TRPV1, TRPV2, TRPA1, TRPV4, and TRPM3 in trigeminal neurons and TRPV1, TRPV2, TRPV3, TRPV4 and TRPM3 in odontoblasts has been revealed. However, their roles as cellular mechanotransducers are controversial and contribution to generation of dental pain is still elusive. This review discusses recent advances in understanding of molecular mechanism underlying development of dental pain.

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