Ligand-induced Dynamic Membrane Changes and Cell Deletion Conferred by Vanilloid Receptor 1

Oláh, Zoltán; Szabó, Tamás; Karai, Laszlo; Hough, Christopher J.; Fields, R. Douglas; Caudle, Robert M.; Blumberg, Peter M.; Iadarola, Michael J.

doi:10.1074/jbc.m008392200

Cited by 223 publications

(273 citation statements)

References 39 publications

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“…RTX is a well-known capsaicin analogue, and its binding is competitively inhibited by the TRPV1 antagonist capsazepine (Szallasi and Blumberg, 1999). RTX treatment can activate TRPV1 and rapidly kill primary afferent neurons through calcium influx and overloading (Olah et al, 2001;Wu et al, 2005). Our immunocytochemistry data confirmed that RTX eliminated presynaptic δ-opioid receptors on TRPV1-immunoreactive DRG neurons and their terminals in the spinal dorsal horn.…”

Section: Discussionsupporting

confidence: 67%

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

Chen

Pan

2008

Neuropharmacology

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Most δ-opioid receptors are located on the presynaptic terminals of primary afferent neurons in the spinal cord. However, their presence in different phenotypes of primary afferent neurons and their contribution to the analgesic effect of δ-opioid agonists are not fully known. Resiniferatoxin (RTX) is an ultra-potent transient receptor potential vanilloid type 1 channel (TRPV1) agonist and can selectively remove TRPV1-expressing primary afferent neurons. In this study, we determined the role of δ-opioid receptors expressed on TRPV1 sensory neurons in the antinociceptive effect of the ]-deltorphin produced a large and prolonged increase in the nociceptive threshold in RTX-treated rats. These findings indicate that loss of TRPV1-expressing afferent neurons leads to a substantial reduction in presynaptic δ-opioid receptors in the spinal dorsal horn. However, the effect of δ-opioid agonists on mechano-nociception is paradoxically potentiated in the absence of TRPV1-expressing sensory neurons. This information is important to our understanding of the cellular sites and mechanisms underlying the spinal analgesic effect of δ-opioid agonists.

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Section: Discussionsupporting

confidence: 67%

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

Chen

Pan

2008

Neuropharmacology

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“…TRPV3 appears to exhibit a similar pattern in skin sections (3), a result we have confirmed. 3 Functional intracellular TRPV1 has been detected in sensory neurons (33)(34)(35) and heterologously transfected cells (36). In urinary epithelial cells, TRPV1 immunoreactivity has also been detected in an intracellular, apparently vesicular compartment (37).…”

Section: Discussionmentioning

confidence: 95%

Warm Temperatures Activate TRPV4 in Mouse 308 Keratinocytes

Chung¹,

Lee²,

Caterina³

2003

Journal of Biological Chemistry

263

211

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Mammalian survival requires constant monitoring of environmental and body temperature. Recently, several members of the transient receptor potential vanilloid (TRPV) subfamily of ion channels have been identified that can be gated by increases in temperature into the warm (TRPV3 and TRPV4) or painfully hot (TRPV1 and TRPV2) range. In rodents, TRPV3 and TRPV4 proteins have not been detected in sensory neurons but are highly expressed in skin epidermal keratinocytes. Here, we show that in response to warm temperatures (>32°C), the mouse 308 keratinocyte cell line exhibits nonselective transmembrane cationic currents and Ca 2؉ influx. Both TRPV3 and TRPV4 are expressed in 308 cells. However, the warmth-evoked responses we observe most closely resemble those mediated by recombinant TRPV4 on the basis of their electrophysiological properties and sensitivity to osmolarity and the phorbol ester, 4␣-phorbol-12,13-didecanoate. Together, these data support the notion that keratinocytes are capable of detecting modest temperature elevations, strongly suggest that TRPV4 participates in these responses, and define a system for the cell biological analysis of warmth transduction.The perception of ambient temperature is a physiological process critical to the maintenance of body temperature and the avoidance of painful or dangerous thermal extremes. Since the identification of the heat-sensing ion channel TRPV1 (1), 1 which is activated by temperatures above 42°C, there has been a significant focus on potential thermosensory functions for this and other ion channels of the transient receptor potential family. TRPV2 (2) and TRPV3 (3-5) were first described as heat transducers operative at very hot (Ͼ52°C) and moderately warm (Ͼ34°C) temperatures, respectively. TRPV4, which was originally identified as an osmosensory ion channel (6 -9), can also be activated by warm temperatures (Ͼ34°C) (10, 11). In addition, two TRP proteins outside of the TRPV subfamily, TRPM8 (12, 13) and ANKTM1 (ankyrin repeat/transmembrane-containing ion channel) (14), have been identified as cold-activated ion channels expressed in sensory neurons.In mammals, the skin is extremely important for the transduction of thermal information and its transmission to the central nervous system. Cutaneous thermosensation has been largely attributed to the sensory nerves that innervate the dermal and epidermal layers of the skin. Recent reports, however, have suggested the possibility that other skin components, most notably keratinocytes, might also participate in temperature sensation. TRPV1 and TRPV2 are highly expressed in distinct subsets of sensory neurons (2). In humans, TRPV3 is also expressed in sensory neurons (5). In contrast, attempts to detect TRPV4 (9, 10) and TRPV3 (3) at the protein level in rodent sensory neurons have been unsuccessful. Rather, immunohistochemical studies of mouse and rat skin have revealed that keratinocytes exhibit the greatest degree of cutaneous TRPV3 (3) and TRPV4 (10) expression. In addition, although peripheral sensory neurons ...

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“…DRG Cultures. Pregnant female rats or mice were killed, and embryos were removed from the uterus at embryonic day 15 (39). Cells were dissociated with 0.125% trypsin͞EDTA in Ca 2ϩ ͞Mg 2ϩ -free Hanks' balanced salt solution (HBSS) for 30 min at 35°C, and an aliquot was stained with trypan blue to count the viable cells.…”

Section: Methodsmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity regulates pain signaling

Pareek

Keller

Kesavapany

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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109

151

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Several molecules and cellular pathways have been implicated in nociceptive signaling, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine͞threonine kinase implicated in the development and disease of the mammalian nervous system. The precise role of this kinase in sensory pathways has not been well characterized. Here we report a molecular role for Cdk5 in nociception. We identified the expression of Cdk5 and its activator p35 in nociceptive neurons, which is modulated during a peripheral inflammatory response. Increased calpain activity in sensory neurons after inflammation resulted in the cleavage of p35 to p25, which forms a more stable complex with Cdk5 and, consequently, leads to elevation of Cdk5 activity. p35 knockout mice (p35 ؊/؊ ), which exhibit significantly decreased Cdk5 activity, showed delayed responses to painful thermal stimulation compared with WT controls. In contrast, mice overexpressing p35, which exhibit elevated levels of Cdk5 activity, were more sensitive to painful thermal stimuli than were controls. In conclusion, our data demonstrate a role for Cdk5͞p35 activity in primary afferent nociceptive signaling, suggesting that Cdk5͞p35 may be a target for the development of analgesic drugs.nociception ͉ inflammation ͉ dorsal root ganglia ͉ trigeminal ganglia ͉ spinal cord P ain is a combination of sensory (discriminative) and affective (emotional) components. The sensory component of pain is defined as nociception and is required for survival and the maintenance of the integrity of the organism. However, sustained or chronic pain, particularly in humans, can result in secondary symptoms such as anxiety, depression, and a marked decrease in the quality of life (1, 2). Specific cell types and several molecules have been identified that detect and regulate nociceptive activity. Additionally, the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain have been elucidated, but the underlying molecular mechanisms remain unclear. So far, studies using genetically modified mice, antisense knockdowns in cells, gene expression assays (including DNA microarray-based expression profiling), and linkage mapping have identified several genes the expression levels of which are directly or indirectly affected during pain sensation and͞or that are involved in modulating pain (3). As a result, the number of proteins encoded by these genes continues to expand, and further investigation of their participation in pain pathways is required.Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (which belong to a family of small proline-directed serine͞threonine kinases), is mainly active in postmitotic neurons because of the selective neuronal expression of its activators, p35 and p39 (4, 5). Transcriptional and translational regulation of p35 and p39 plays a key role in the maintenance of normal Cdk5 activity. We and others have previously reported critical role...

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Ligand-induced Dynamic Membrane Changes and Cell Deletion Conferred by Vanilloid Receptor 1

Cited by 223 publications

References 39 publications

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

Warm Temperatures Activate TRPV4 in Mouse 308 Keratinocytes

Cyclin-dependent kinase 5 activity regulates pain signaling

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