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Αcgrp Is Essential for Algesic Exocytotic Mobilization of TRPV1 Channels in Peptidergic Nociceptors

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Αcgrp Is Essential for Algesic Exocytotic Mobilization of TRPV1 Channels in Peptidergic Nociceptors αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors Isabel Devesaa, Clotilde Ferrándiz-Huertasa, Sakthikumar Mathivanana, Christoph Wolfa, Rafael Lujánb, Jean-Pierre Changeuxc,d,1, and Antonio Ferrer-Montiela,e,1 aInstituto de Biología Molecular y Celular, Universidad Miguel Hernández, 03202 Elche, Spain; bDepartment Ciencias Médicas, Instituto de Investigación en Discapacidades Neurológicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006 Albacete, Spain; cCollège de France, 75005 Paris, France; dInstitut Pasteur, Centre National de la Recherche Scientifique, Unité de Recherche Associée, 7506 Paris, France; and eUnidad de Biofísica, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Consejo Superior de Investigaciones Científicas, 48940 Leioa, Spain Contributed by Jean-Pierre Changeux, October 31, 2014 (sent for review August 12, 2014) Proalgesic sensitization of peripheral nociceptors in painful syn- LDCVs can also serve as carriers of a plethora of signaling dromes is a complex molecular process poorly understood that molecules, including ion channels and receptors that may enable involves mobilization of thermosensory receptors to the neuronal fast modulation of neuronal excitability (23). This finding raises surface. However, whether recruitment of vesicular thermoTRP the exciting hypothesis that proalgesic recruitment of TRPV1 channels is a general mechanism underlying sensitization of all channels is a mechanism occurring in peptidergic nociceptors. nociceptor types or is subtype-specific remains controversial. We We used ATP, a well-known proalgesic agent (24–26), to in- + report that sensitization-induced Ca2 -dependent exocytotic inser- vestigate the mechanisms underlying TRPV1 sensitization in tion of transient receptor potential vanilloid 1 (TRPV1) receptors to sensory neurons. We report that ATP-induced TRPV1 potenti- the neuronal plasma membrane is a mechanism specifically used ation in peptidergic nociceptors specifically involves the exo- cytotic mobilization of new channels to the cell surface. Notably, by peptidergic nociceptors to potentiate their excitability. Notably, α we found that TRPV1 is present in large dense-core vesicles knockout of CGRP expression inhibited the ATP-evoked TRPV1 (LDCVs) that were mobilized to the neuronal surface in response delivery to the neuronal surface and prevented ATP-induced in vivo thermal hyperalgesia. Thus, algesic-induced exocytosis of to a sensitizing insult. Deletion or silencing of calcitonin-gene– TRPV1 channels in peptidergic nociceptors is a central mecha- related peptide alpha (αCGRP) gene expression drastically reduced NEUROSCIENCE nism in pain signaling. proalgesic TRPV1 potentiation in peptidergic nociceptors by abro- 2+ gating its Ca -dependent exocytotic recruitment. These findings Results uncover a context-dependent molecular mechanism of TRPV1 alge- TRPV1 Sensitization in Peptidergic Nociceptors Requires Receptor sic sensitization and a previously unrecognized role of αCGRP in Exocytosis. ATP-induced TRPV1 sensitization in peptidergic, − LDCV mobilization in peptidergic nociceptors. Furthermore, these IB4-negative (IB4 ) nociceptors from rat dorsal root ganglia results imply that concurrent secretion of neuropeptides and chan- (DRG) was evaluated in neuronal cultures depleted of non- + nels in peptidergic C-type nociceptors facilitates a rapid modula- peptidergic, IB4-positive (IB4 ) with the toxin IB4-saporin. A short tion of pain signaling. incubation of saporin-treated nociceptor cultures with 10 μMof ATP resulted in a 3.8-fold potentiation of desensitized capsaicin pain transduction | nociception | ion channel | inflammation | responses (Fig. 1 A–C) and a 53 ± 8% augmentation in the sensory neuron number of sensitized neurons (SI Appendix, Table S1). Exposure ransient receptor potential vanilloid 1 (TRPV1) is a non- Significance Tspecific cationic channel activated by capsaicin, noxious heat, acid pH, voltage, and membrane-derived lipids (1). TRPV1 Pain is a societal burden with enormous economic and social upregulation in sensory neurons is a key element in pain de- costs. More than 50% of pain patients find current therapies velopment and maintenance of several pathological chronic unsatisfactory. A major reason for this pharmacological failure – conditions (2 5). Its contribution to thermal hyperalgesia has is our limited understanding of the cellular processes un- been well-defined through pharmacological and knockout stud- derlying pain. Algesic sensitization of nociceptors is a complex ies (6, 7). TRPV1 channel is subject to a complex regulation by event in pain transduction that involves the potentiation of proalgesics that potentiate its activity through modulation of its thermosensory channels. The molecular mechanisms remain gating properties (8, 9) and/or by increasing the expression of new controversial because of nociceptor heterogeneity that sug- channels into the neuronal surface (10, 11). Whether these mech- gests the existence of cell-type–specific strategies. We show anisms are a general means to sensitize TRPV1 in all nociceptor that algesic sensitization of transient receptor potential vanil- subpopulations or are cell-type–specific remains contentious. loid 1 (TRPV1) involves the exocytotic recruitment of new TRPV1 is widely expressed in peptidergic and nonpeptidergic receptors in peptidergic nociceptors and the modulation of nociceptors from the neonatal and adult rat peripheral nervous channel gating in nonpeptidergic sensory neurons. Further- system (12, 13). In mice, TRPV1 is transiently present in a wider more, algesic delivery of TRPV1 channels is concomitant with range of sensory neurons during development, but its expression pro-inflammatory neuropeptide secretion, ensuring rapid mod- gradually becomes restricted to the peptidergic subpopulation ulation of pain transduction. in adult animals (14, 15). The presence of TRPV1 in C-type peptidergic nociceptors is readily evidenced by its colocalization Author contributions: A.F.-M. designed research; I.D., C.F.-H., S.M., and C.W. performed with the main proinflammatory neuropeptides calcitonin-gene– research; R.L. and J.-P.C. contributed new reagents/analytic tools; I.D., C.F.-H., S.M., and related peptide alpha (αCGRP) and substance P (SP) (16, 17). C.W. analyzed data; and I.D. and A.F.-M. wrote the paper. αCGRP and SP are pivotal to develop and maintain neurogenic Conflict of interest statement: A.F.-M. is an inventor of patent WO2010 009892, protect- pain and inflammation as genetic ablation of these peptides ing the antinociceptive activity of compound DD04107. results in pain resistance (18–21). These neuropeptides are se- Freely available online through the PNAS open access option. lectively stored in large dense-core vesicles (LDCVs) and are 1To whom correspondence may be addressed. Email: [email protected] or [email protected]. released in response to proalgesic stimuli through a regulated, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 2+ Ca -dependent, and SNARE-mediated secretory pathway (22). 1073/pnas.1420252111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1420252111 PNAS | December 23, 2014 | vol. 111 | no. 51 | 18345–18350 Downloaded by guest on September 27, 2021 − − − − of cultures to IB4-saporin reduced ATP-induced TRPV1 po- (αCGRP / ×Tac1 / , referred to as DKO) by breeding the single- tentiation by 30% (Fig. 1 B and C) and the number of sen- knockout mice (18, 20) (SI Appendix,Fig.S2A). Under physiological sitized neurons by 55% (SI Appendix, Table S1). Notably, conditions, the distribution of nociceptor subpopulations was un- incubation of nociceptors with 20 μM DD04107, a palmitoylated altered in DKO mice (SI Appendix, Table S2). Similarly, TRPV1 peptide that inhibits neuronal exocytosis (11), decreased ATP- expression and its cellular location was not affected, being evoked TRPV1 sensitization by 27% and 50% in saporin and primarily expressed in small-to-medium peptidergic nociceptors IB4-saporin–treated primary cultures, respectively (Fig. 1 A–C) (SI Appendix, Fig. S2 B and C). Moreover, TRPV1-expressing without affecting the number of sensitized neurons (SI Appendix, sensory neurons displayed similar electrical properties in wild- Table S1). type (WT) and DKO mice (SI Appendix, Table S3), and TRPV1 − + ATP-induced TRPV1 potentiation in IB4 and IB4 noci- activity was not altered as evidenced by the similar number of ceptors was also investigated by patch clamp using IB4-alexa 568 nociceptors responding to capsaicin (25 ± 4% WT and 23 ± 5% + to label IB4 nociceptors. Capsaicin-induced ionic currents in DKO nociceptors) and their comparable EC for the vanilloid (SI − + 50 IB4 and IB4 nociceptors were similarly potentiated by 10 μM Appendix,Fig.S2D). Therefore, these DKO mice represent an ATP (Fig. 1 D–F). Notably, ATP-induced TRPV1 sensitization in appropriate model for examining the contribution of αCGRP and − IB4 sensory neurons was blocked by 100 μM of nonpalmitoylated SP to ATP-induced TRPV1 sensitization in peptidergic nociceptors. DD04107 delivered to the neuronal cytosol through the pipette We next examined ATP-mediated TRPV1 potentiation in (Fig. 1 D, Bottom,andF). In contrast, ATP potentiation of TRPV1 DKO nociceptors. As illustrated in Fig. 2 C–E, incubation of + in IB4 nociceptors was insensitive to the peptide (Fig. 1 E, Bottom, capsaicin-desensitized neuronal cultures with ATP promoted fast and F). Taken together, these results
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