GRIP1 regulates AMPA receptor targeting to dendrites and the recycling of AMPA receptors to the plasma membrane following NMDA receptor (NMDAR) activation (Setou et al., 2002 and Mao et al., 2010). We, therefore, hypothesized that GRIP1b palmitoylation might in turn affect GRIP1b’s ability to regulate AMPA receptor recycling. To address this possibility, we transfected hippocampal neurons with wild-type, nonpalmitoylatable, or constitutively membrane-targeted forms of GRIP1b, together with a pHluorin-tagged GluA2 AMPA receptor, to which GRIP1 directly binds (Dong et al., 1997 and Mao et al., 2010). The pHluorin tag fluoresces

brightly at neutral pH, as when the receptor www.selleckchem.com/HIF.html is present on the plasma membrane. Brief treatment with NMDA drives internalization PD0325901 of pHGluA2 to recycling endosomes, whose acidity (pH <6.6) dramatically quenches pHGluA2 fluorescence, while NMDA washout induces pHGluA2 recycling to the plasma membrane and fluorescence recovery (Ashby et al., 2004, Lin and Huganir, 2007, Thomas et al., 2008 and Mao et al., 2010; Figure 6A). Fluorescence of pHGluA2,

therefore, acts as a readout of receptor distribution and can be used to determine rates and degrees of internalization and recycling. In particular the T1/2 of fluorescence recovery time, derived from a single exponential fit of the recycling phase, provides a quantitative measure of recycling rate. In neurons transfected with GRIP1bwt or GRIP1bC11S, rates of pHGluA2 internalization and recycling were highly similar to neurons transfected with vector alone (Figure 6B). However, pHGluA2 Mephenoxalone recycling was markedly accelerated in neurons transfected with Myr-GRIP1b (Figure 6C). This accelerated recycling was also seen in neurons transfected with

DHHC5, which is predicted to increase palmitoylation of endogenous GRIP1b (Figures 6D and Figures S5A). Both Myr-GRIP1b and DHHC5 caused accelerated recycling of both somatic and dendritic pHGluA2 (Figures 6 and Figures S5B–S5E). The effect of transfected DHHC5 is likely due to direct palmitoylation of GRIP1b, as although GluA2 is a known palmitoylated protein (Hayashi et al., 2005), it is not detectably palmitoylated by DHHC5 (Figure S5B). AMPA receptor recycling is, therefore, significantly accelerated under conditions where GRIP1b membrane attachment is enhanced (Figures 6E and Figures S5E). Myr-GRIP1b, which is targeted to trafficking vesicles, also colocalized extensively with pH-GluA2 in dendritic puncta in fixed neurons (Figure S5C), suggesting that effects on trafficking were likely due to a direct GRIP1b-pHGluA2 interaction. Here, we report that two PATs use a novel PDZ domain recognition mechanism to palmitoylate and control the distribution and trafficking of GRIP1b.

Furthermore, the EGFP-positive fibers in the liver appear to be osmosensitive as they exhibit robust increases in pERK staining after intake of 1 ml water in transgenic mice ( Figure 5D). In Ca2+-imaging experiments a striking 53% of the acutely isolated thoracic EGFP-positive neurons responded to the 230 mOsm stimulus (41/77 neurons), a significantly

higher proportion than found in EGFP-negative thoracic neurons (15%, 21/140 neurons) and of nonselected neurons in wild-type mice (31%, 62/217 neurons), p < 0.01 and p < 0.05 chi-square test ( Figure 5E). Thus, osmosensitive neurons are enriched within the population of EGFP-positive thoracic DRGs many of which innervate the liver. However, though very supportive, these results did not clarify whether cells that give rise to this website pERK-positive fibers in vivo and cells that are osmosensitive in cultures constitute the same subpopulation of thoracic DRG neurons. To test directly whether thoracic neurons with an osmosensitive current are hepatic osmoreceptors, we retrogradely labeled hepatic sensory neurons by injecting click here an Alexa Fluor-488 conjugated dextran amine into the liver. Three to four days after tracer injection into the liver, the thoracic ganglia were isolated and whole-cell patch-clamp recordings made from identified hepatic afferent neurons (Figure 6A). As a control for tracer leakage, DRGs were cultured from nearby spinal segments, but no labeled neurons were found. Strikingly,

almost all the hepatic afferent neurons 91.3% (21/23 cells) possessed a fast inward current in response to local perfusion of a 260 mOsm hypo-osmotic

solution (Figures 6A and 6B, green bars). The proportion too of osmosensitive neurons among the labeled hepatic afferent neurons (21/23 cells) was significantly higher than that found in randomly selected neurons from T7–T13 DRGs (25/37 cells, p < 0.05; Student’s unpaired t test; Figure 6B, black bars). In contrast, identified hepatic afferent neurons from Trpv4−/− mice only infrequently exhibited an inward current to hypo-osmotic stimulation 31.6% (6/19 cells), significantly different from wild-type neurons 91.3% (21/23 cells) chi-square test p < 0.01. Interestingly, the remaining osmosensitive currents found in Trpv4−/− mice were kinetically indistinguishable from those found in wild-type mice ( Figure S2). However, closer inspection of osmosensitive and nonosmosensitive neurons revealed that these two classes of neurons were also different in other respects. Identified hepatic sensory neurons that had lost their osmosensitivity in Trpv4−/− mice were significantly smaller (23.9 ± 0.8 μm versus 35 ± 1.6 μm, p < 0.001, Student’s paired t test) and had wider action potentials (3.35 ± 0.18 ms versus 1.60 ± 0.11 ms, p < 0.001, Student’s paired t test) than neurons that retain their osmosensitivity. Moreover, the small TRPV4-dependent osmosensitive neurons were more excitable as they fired an average of 2.9 ± 0.

However, this interpretation is unlikely because we continue to observe activity in the insula when participants match expectations after controlling for the amount of money that participants chose to return.

To provide further support for our interpretation that the competing motivations to maximize financial gain and minimize anticipated guilt are associated with distinct regions, we examined the relationship between the regions of interest (as defined by the group analyses) and independently assessed individual differences in guilt sensitivity. Consistent with our interpretation, click here we find that participants who report that they would have experienced more guilt had they returned less money demonstrated increased insula and SMA activation when they matched expectations. Conversely, participants who claimed that they would not have experienced any additional guilt had they returned less money showed increased activity in the NAcc when they in fact returned less than they believed their partner expected them to return. This implies that there

is individual variability in the way in which anticipated guilt influences decisions. People who are more guilt sensitive have increased activity in the network associated with moral sentiments, while people with less guilt sensitivity have greater activity in those areas associated with reward and value. Together, our results suggest that participants who are guilt sensitive may experience moral sentiments via the insula

and Alectinib mw SMA, which signals that they will feel guilty if they believe they let their investment partner down. This notion that feelings can be used as information in the decision-making process Thiamine-diphosphate kinase has been discussed in other domains of decision making such as risk (Damasio, 1994, Loewenstein et al., 2001, Mellers et al., 1997 and Slovic et al., 2002) and regret (Coricelli et al., 2005). According to this framework, people generate anticipated emotions about how they might feel after choosing a particular outcome, which ultimately predicts their decision (Mellers et al., 1997). Interestingly, anticipatory feelings associated with risk have been reliably associated with the anterior insula (Critchley et al., 2001) and ACC (Coricelli et al., 2005), which provides further support for our argument that guilt aversion is generated by a sampling of the sentiment in question and is processed by the cingulo-insular network. Importantly, this extends the notion of anticipatory emotions from individual decision making to social contexts. These feelings originating in the insula may recruit the DLPFC to override the competing motivation to maximize financial gain and overall result in participants honoring their partner’s trust and returning their initial investment.

We first determined whether there was a disruption in the developmental switch from NR2B to NR2A in layer 2/3. We made whole-cell patch-clamp

recordings from layer 2/3 pyramidal neurons in slices of primary visual cortex and found that NMDA EPSCs elicited by layer 4 stimulation exhibited longer decay times and greater ifenprodil sensitivity in mGluR5 knockouts compared to wild-type (Figures 6E–6H). This indicates a deficiency in the development switch from NR2B to NR2A-containing receptors. Visual experience in dark-reared rodents causes a rapid switch from NR2B- to NR2A-containing NMDARs at layer 4 inputs onto layer 2/3 pyramidal neurons in primary visual cortex that depends upon NMDAR activation (Philpot see more et al., 2001 and Quinlan et al., 1999). Therefore, we next tested whether this experience-dependent plasticity is disrupted in mGluR5 knockout mice. We dark reared wild-type mice and mGluR5 knockout littermates from P6 until P17–P19, exposed some of these animals to 2.5 hr of light, and then investigated

the effects on NMDA EPSCs at layer 4 inputs onto layer 2/3 pyramidal cells. In wild-type mice NMDA EPSCs in animals exposed to light (+LE) exhibited faster kinetics and reduced ifenprodil sensitivity compared to mice that did not receive light exposure (Figures 7A–7E). The degree Fasudil of change in these parameters was very similar to that previously reported (Philpot et al., 2001 and Quinlan et al., 1999) and confirms that over even brief exposure to light can drive the switch from NR2B to NR2A in visual cortex. In mGluR5 knockout

mice light exposure failed to produce any significant change in NMDA EPSC kinetics or ifenprodil sensitivity (Figures 7A–7E). It was also noticeable that the dark-reared wild-type and knockout mice (that were not exposed to light) exhibited very similar NMDA EPSC kinetics and ifenprodil sensitivity, indicating that visual experience and mGluR5 are necessary for the developmental change from NR2B to NR2A-containing NMDARs in visual cortex during the first few postnatal weeks. During the first postnatal week, most cortical synapses express NR2B-containing receptors, whereas later in development (>P14), many of these receptors are replaced with NR2A-containing NMDARs. Synaptic activity is involved in regulating this switch, and a role for sensory experience in primary sensory cortex has also been demonstrated; however, the molecular mechanisms driving this ubiquitous NMDAR subtype switch have hitherto been largely unexplored. Here, we find that activation of both mGluR5 and NMDARs is required for this switch to occur at synapses on hippocampal CA1 pyramidal neurons. Furthermore, we define a downstream signaling pathway involving PLC activation, release of Ca2+ from IP3R-dependent stores, and activation of PKC (see Figure 8 for model).

To induce LTD, we subjected the slices to DHPG bath application (100 μM, 5 min) 30 min after breaking into the cells. LTD was observed in cells infused with control mismatch siRNA ( Figures 7F–7H). In contrast, DHPG failed to induce LTD in neurons infused with Ophn1#2 siRNA. Note, all LTD experiments were performed within the same slice using two simultaneous patch-clamp recordings of neighboring CA1 cells; each pipette was filled with learn more one of the siRNAs. Together, these data indicate that rapid synthesis of OPHN1 is necessary for mGluR-LTD. Noteworthy, previous studies demonstrated that mGluR-LTD persists in the

absence of protein synthesis in Fmr1 KO mice ( Hou et al., 2006 and Nosyreva and Huber, 2006). Our data indicate

that mGluR-induced OPHN1 synthesis is independent of FMRP ( Figure 1G), raising the question as to whether mGluR-LTD in Fmr1 KO mice still requires OPHN1 synthesis. To address this, we introduced Ophn1#2 siRNA, or mismatch siRNA, into CA1 neurons of acute hippocampal slices prepared from Fmr1 KO and corresponding wild-type mice, and subjected the slices to DHPG bath application 30 min after breaking into the cells. LTD was observed in both wild-type and Fmr1 KO this website cells infused with the control mismatch siRNA ( Figures 8A and 8B), which consistent with previous reports was protein synthesis dependent in wild-type, but not Fmr1 KO neurons (data not shown). Interestingly, whereas DHPG-induced LTD was inhibited in wild-type neurons infused with Ophn1#2 siRNA, LTD was not affected in Fmr1 KO neurons infused with the Ophn1#2 siRNA ( Figures 8A and 8B). These data indicate that OPHN1 synthesis is required for mGluR-LTD in wild-type, but not Fmr1 KO mice. Likely, the elevated/aberrant protein synthesis caused by loss GBA3 of FMRP can compensate for the requirement of new synthesis of OPHN1. A common feature for mGluR-LTD in many brain regions is the reliance on rapid and local protein synthesis (Lüscher and Huber, 2010 and Waung and Huber, 2009). The identities of the newly synthesized proteins that mediate LTD, however, remain largely elusive, with Arc/Arg3.1

being the leading candidate ‘LTD protein’ in the hippocampal CA1 area (Park et al., 2008, Waung and Huber, 2009 and Waung et al., 2008). Our study identifies the X-linked mental retardation protein, OPHN1, as a new molecule that is rapidly synthesized upon activity and is required for mGluR-LTD in the hippocampus. Importantly, the role of OPHN1 in mediating mGluR-LTD can be molecularly dissociated from its role in basal AMPAR-mediated synaptic transmission (Nadif Kasri et al., 2009). Whereas the former requires OPHN1′s interaction with Endo2/3, the latter requires OPHN1′s Rho-GAP activity and interaction with the Homer 1b/c proteins (Figure 8C). Our results provide several lines of evidence for rapid dendritic synthesis of OPHN1 in response to group I mGluR stimulation in the hippocampal CA1 area.

, 2010). Our data demonstrate that mechanoreceptor currents in ASH are carried by two genetically separable currents, but we do not know whether force activates these two currents this website in a sequential or parallel fashion. In any plausible sequential model, the minor current must be upstream of the major current because it remains when deg-1 is lost and thus its activation must precede activation of the major current. But, the minor current does not activate faster than the total current. Also, if the major deg-1-dependent current were activated in response to the minor current, this event must be complete in milliseconds or less. Most second messenger systems are not that rapid. While we cannot eliminate

the sequential model, we favor the parallel model and propose that ASH expresses two sensory mechanotransduction channel complexes, one of which uses DEG-1 as a pore-forming subunit. The use of multiple mechanotransduction channels may not be unique to ASH; other mechanoreceptor neurons may express multiple classes of mechanotransduction channels ( Göpfert et al., 2006 and Walker et al., 2000). This functional redundancy could account for difficulties in identifying a single channel type responsible for mechanoreceptor currents in mammalian somatosensory neurons, including nociceptors. Most animals are endowed with a complex array of sensory neurons specialized to detect mechanical energy in the form of touch, vibration, or

body movements. Such neurons vary not only in the loads and strains they detect, but also in their sensitivity. In the present work and in a prior study (O’Hagan et al., 2005), we have shown that two kinds of C. elegans Volasertib ic50 mechanoreceptor neurons, ASH and PLM neurons, respond to force

using channels formed by DEG/ENaC proteins. The two kinds of neurons differ in their sensitivity to mechanical loads: nearly one hundred-fold higher forces are required to activate mechanoreceptor currents in ASH nociceptors (this study) than in the PLM touch receptor neurons ( O’Hagan et al., 2005). The difference in sensitivity could reside in the MeT channels themselves. In this scenario, each DEG/ENaC subunit would harbor a force sensor that links mechanical loads to channel gating, but the sensors would vary in the forces required to activate them. Alternatively, below the primary determinant of force sensitivity could be the cellular machinery that transmits loads from the body surface to the channel proteins embedded in the sensory neuron’s plasma membrane. These two modes for establishing the exact force dependence of MeT channels in vivo are not mutually exclusive, however. Regardless of the molecular and cellular basis for the difference in sensitivity, our work establishes that both low-threshold, gentle touch receptor neurons and high-threshold nociceptors rely on DEG/ENaC proteins to form amiloride-sensitive, sodium-permeable channels responsible for MRCs in vivo.

These records estimated the annual economic costs for each facility for cold chain, human resources, and transport. Additional cost metrics included total cost per dose delivered, long-term costs, and cost savings. The 2009 Benin comprehensive multiyear plan

(cMYP) was used to supplement the cost estimates. Each geographic location in the supply chain was determined using a combination of data received from the country and location searches on Google Maps. The total recurring logistics operating costs per year for the vaccine supply chain came from the following formula: costtotal=costlabor+coststorage+costtransport+costbuilding, wherecosttotal=costlabor+coststorage+costtransport+costbuilding, where Crizotinib mw costlabor=Σemployees costper employeecostlabor=Σemployees costper employee coststorage=Σstorage device units costper storage device unitcoststorage=Σstorage device units costper storage device unit CP-868596 solubility dmso costtransport=Σtransport routes costper transport routecosttransport=Σtransport routes costper transport route costbuilding=Σbuildings costper buildingcostbuilding=Σbuildings costper building

The following expressions define the annual recurring unit cost for each of the categories: • Annual Unit Labor Costs costper employee=costemployee’s annual salary and benefits×% of time dedicated to vaccine logisticscostper employee=costemployee’s annual salary and benefits×% of time dedicated to vaccine logistics Building costs were based on information from the cMYP, and per diems were based on conversations with an in-country professional reference. The model included Benin’s seven current World Health Organization (WHO) EPI vaccines (Appendix A). To explore NVI we modeled scenarios with the Rotarix rotavirus vaccine (Rota) introduced into the routine vaccination schedule. As the size of this presentation is similar to other potential introductions, such as the meningococcal vaccine or Tolmetin the human papilloma virus vaccine (HPV), the

results can be considered relevant to these planned NVIs. Benin’s vaccine supply chain operates as a four-level delivery system: the first level is the National Depot, the second level is composed of six Department Stores and one Regional Store (operating in the same fashion as a Department Store), the third level consists of 80 Commune Stores, and the fourth of several hundred Health Posts (Fig. 1a.) The National Depot delivers vaccines via cold truck to some Department Stores, while the remaining Department Stores use 4 × 4 trucks to pick up vaccines from the National Depot. All Communes pick up vaccines from the Department Stores using 4 × 4 trucks, and all Health Posts pick up vaccines from the Communes using motorbikes.

Firstly, vaccination may reduce the individual’s susceptibility to acquisition of colonisation. In general, susceptibility to acquisition is quantified by the rate of acquisition in those not colonised or otherwise considered susceptible to acquire the target (vaccine) serotypes (cf. [11] and [15]).

Metformin Secondly, vaccination may enhance the clearance of colonisation so that duration of future colonisation is shortened. Thirdly, vaccination may decrease the density of future colonisation, i.e. the quantitative load of pneumococcal carriage in the nasopharynx, as compared to a non-vaccinated carrier. All these three primary endpoints (acquisition, duration, density) can be considered either specific to the individual protective components of the vaccine or “overall” in an aggregate manner. For example, for PCVs, the serotypes included in a vaccine formulation can be considered PLX4032 in vitro either individually or as a set of all vaccine serotypes. Although the main interest often lies in estimating the aggregate efficacy against all vaccine serotypes, vaccine effects on non-vaccine serotypes are also important if serotype replacement is considered (see Section 3). In addition to the primary endpoints,

various summary endpoints can be used to quantify vaccine effects on colonisation. In particular, a combined endpoint involving both acquisition and duration proves to have many desirable epidemiological properties. It is defined as T = (hazard rate of acquisition) × (mean duration of colonisation).

The risk of T is related to a susceptible individual’s expected (i.e. future) time spent colonised and thereby capable of spreading the organism. If transmissibility varies over the course of the colonisation episode, T is only an approximation of an individual’s capacity to spread pneumococci. tuclazepam However, even in this case T is likely to offer a feasible measure of transmission potential (cf. [16]). Moreover, if the density of colonisation is associated with both the transmissibility and the sensitivity of detection of colonisation, T reflects the transmission potential even without factoring density explicitly in this parameter. Finally, vaccine efficacy based on T can be estimated from cross-sectional data under weak assumptions about the colonisation processes in the study subjects, which makes it a particularly useful endpoint (see Section 4 for further discussion on this issue). There is evidence for current PCVs reducing a vaccinated individual’s susceptibility to acquisition of pneumococcal serotypes included in the vaccine formulation. This has been shown most clearly by studies addressing the effect of vaccination on early acquisition in infants. Lower levels of VT colonisation prevalence among the vaccinated infants as compared to the controls have been reported soon after immunisation, i.e.

We will return to this notion at the end of this review. Color Inputs to V4. Color vision begins with the L, M, and

S cones in the retina. The cone names derive from their peak wavelength (at 562 nm, 535 nm, 440 nm, respectively). Selleckchem Pazopanib The cone classes do not correspond to our perception of “red” “green” and “blue”; rather, our perception of color requires multiple stages of L, M, S input integration ( Chatterjee and Callaway, 2003, Gegenfurtner and Kiper, 2003, Solomon and Lennie, 2007 and Conway et al., 2010). An important early stage is the generation of color-opponency: red-green neurons detect differences in L and M cone inputs, blue-yellow neurons compare S and L+M inputs, and light-dark neurons sum L and M cone inputs. These comparisons form the two cardinal color axes and orthogonal luminance axis, and are represented by discrete classes of neurons in the lateral geniculate nucleus ( Derrington

et al., 1984). Within V1, color GSK J4 mw opponency is further elaborated and is dominated by cells with responsiveness along the blue-yellow and red-green axes ( Dow and Gouras, 1973, Livingstone and Hubel, 1984, Ts’o and Gilbert, 1988, Lennie et al., 1990, Hanazawa et al., 2000, Conway, 2001, Conway and Livingstone, 2006 and Xiao et al., 2007). While V1 plays an important role in generating color, it does not contain a representation corresponding to perception (e.g., perception of hues, color constancy, Brouwer and Heeger, 2009 and Parkes et al., 2009). It is not until V2 that the first evidence for hue maps (i.e., red, orange, yellow, green, blue, purple, etc.) arises; these hue maps are found in V2 thin stripes ( Xiao et al., 2003). An important open question concerns the mechanisms that transform the cone signals into neurons that code hue, and whether the

color-tuned neurons in V4 inherit their color preferences or compute them within V4 ( Conway, 2009). Brightness. Both color and achromatic brightness (light-dark) are important stimulus features that define object surfaces. Brightness perception is subject to many of the same types of contextual ever influences as color perception (e.g., filling in, Krauskopf, 1963; contextual effects such as lightness constancy and color constancy effects, MacEvoy and Paradiso, 2001; edge-induced percepts such as Cornsweet brightness illusion, Roe et al., 2005, and water color illusion, Pinna et al., 2001). As shown by human functional imaging ( Engel and Furmanski, 2001) and electrophysiological studies in monkeys ( Livingstone and Hubel, 1984 and Roe and Ts’o, 1995), at the level of V1, evidence suggests that color and brightness are largely encoded independently. Little is known about brightness representation in V4.

R.K.), National Institute of Health grant NS053415 (to Y.-B.C.), and the Simons Foundation (to E.R.K, Y.-B.C., and C.H.B.). “
“The detection and rapid avoidance of noxious thermal stimuli is crucial for survival (Basbaum et al., 2009). Both painful and innocuous thermal stimuli are conveyed by primary afferent sensory neurons that innervate skin and mouth and have their cell bodies in the trigeminal (TG) and dorsal root ganglia (DRG) (Basbaum et al., 2009 and Caterina, 2007). Accumulating C59 in vitro evidence indicates that the detection of thermal stimuli in mammals strongly depends on the activation of temperature-sensitive

nonselective cation channels of the TRP superfamily (Bandell et al., 2007, Basbaum et al., 2009, Caterina, 2007 and Talavera et al., 2008). TRPM8 and TRPA1 were shown to be activated by cooling (McKemy et al., 2002, Peier et al., 2002a and Story et al., 2003) and to mediate cold responses in TG and DRG neurons (Bautista et al., 2007, Colburn et al., 2007, Dhaka et al.,

2007 and Karashima et al., 2009). Consequently, knockout mice lacking either TRPM8 or TRPA1 exhibit specific behavioral deficits in response to cold stimuli (Bautista et al., 2007, Colburn et al., 2007, Dhaka et al., 2007, Kwan et al., 2006 and Nilius Sirolimus chemical structure and Voets, 2007), although the involvement of TRPA1 in cold sensing in vivo remains a matter of debate (Bautista et al., 2006, Karashima et al., 2009, Knowlton et al., 2010 and Kwan et al., 2006). Oppositely, four members of the TRPV subfamily, TRPV1–4, are activated upon heating (Caterina et al., 1997, Caterina et al., 1999, Chung et al., 2003, Güler et al., 2002, Peier et al., 2002b, Smith et al., 2002, Watanabe et al., 2002 and Xu et al., 2002). TRPV1, a heat and capsaicin sensor expressed in nociceptor neurons is involved in detecting heat-evoked pain, particularly in inflamed tissue (Caterina et al., 1997, Caterina et al., 2000, Davis et al., 2000 and Tominaga

et al., 1998). The related TRPV3 and TRPV4 are strongly expressed in skin keratinocytes, ADP ribosylation factor and have been mainly implicated in sensing innocuously warm temperatures (Chung et al., 2003, Chung et al., 2004, Lee et al., 2005, Moqrich et al., 2005, Peier et al., 2002b, Smith et al., 2002 and Xu et al., 2002). TRPV2 is activated by extreme heat (>50°C) (Caterina et al., 1999), and has been considered as a potential molecular candidate to explain the activation of TRPV1-deficient sensory neurons at temperatures above ∼50°C, as well as the residual nocifensive response to noxious heat stimuli in TRPV1-deficient mice (Caterina et al., 2000). However, it remains to be established whether TRPV2 functions as a thermosensor in vivo, as deficits in detecting noxious heat have not yet been described for TRPV2-deficient mice. Moreover, it has been clearly demonstrated that a large fraction of heat-sensitive nociceptors lack expression of both TRPV1 and TRPV2 (Woodbury et al., 2004).