Transient Receptor Potential Cation Channel V1 (TRPV1) Is Degraded by Starvation- and Glucocorticoid-Mediated Autophagy

다국어 초록 (Multilingual Abstract)

A mammalian cell renovates itself by autophagy, a pro-cess through which cellular components are recycled to produce energy and maintain homeostasis. Recently, the abundance of gap junction proteins was shown to be regulated by autophagy during starvation conditions, suggesting that transmembrane proteins are also regulated by autophagy. Transient receptor potential vanilloid type 1 (TRPV1), an ion channel loca-lized to the plasma membrane and endoplasmic reticu-lum (ER), is a sensory transducer that is activated by a wide variety of exogenous and endogenous physical and chemical stimuli. Intriguingly, the abundance of cellular TRPV1 can change dynamically under pathological conditions. However, the mechanisms by which the protein levels of TRPV1 are regulated have not yet been explored. Therefore, we investigated the mechanisms of TRPV1 recycling using HeLa cells constitutively expressing TRPV1. Endogenous TRPV1 was degra-ded in starvation conditions; this degradation was blocked by chloroquine (CLQ), 3MA, or downregulation of Atg7. Interestingly, a glucocorticoid (cortisol) was capable of inducing autophagy in HeLa cells. Cortisol increased cellular conversion of LC3-I to LC-3II, leading autophagy and resulting in TRPV1 degradation, which was similarly inhibited by treatment with CLQ, 3MA, or downre-gulation of Atg7. Furthermore, cortisol treatment induced the colocalization of GFP-LC3 with endogenous TRPV1. Cumulatively, these observations provide evidence that degradation of TRPV1 is mediated by autophagy, and that this pathway can be enhanced by cortisol.

참고문헌 (Reference)

1 Fukuoka, T., "VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation" 99 : 111-120, 2002

2 Hudson, L. J., "VR1 protein expression increases in undamaged DRG neurons after partial nerve injury" 13 : 2105-2114, 2001

3 Gallego-Sandin, S., "The endoplasmic reticulum of dorsal root ganglion neurons contains functional TRPV1 channels" 284 : 32591-32601, 2009

4 Caterina, M. J., "The capsaicin receptor : a heat-activated ion channel in the pain pathway" 389 : 816-824, 1997

5 Kim, Y. H., "TRPV1 in GABAergic interneurons mediates neuropathic mechanical allodynia and disinhibition of the nociceptive circuitry in the spinal cord" 74 : 640-647, 2012

6 Goswami, C., "TRPV1 expression-dependent initiation and regulation of filopodia" 103 : 1319-1333, 2007

7 Szallasi, A., "TRP ion channel function in sensory transduction and cellular signaling cascades" Boca Raton 2007

8 Clapham, D. E., "TRP channels as cellular sensors" 426 : 517-524, 2003

9 Settembre, C., "Signals from the lysosome : a control centre for cellular clearance and energy metabolism" 14 : 283-296, 2013

10 Wallace, A. D., "Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids" 276 : 42714-42721, 2001

11 Jung, J., "Phosphorylation of vanilloid receptor 1 by Ca2+/ calmodulin-dependent kinase II regulates its vanilloid binding" 279 : 7048-7054, 2004

12 Kabeya, Y., "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing" 19 : 5720-5728, 2000

13 Kanai, Y., "Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats" 49 : 977-984, 2005

14 Fong, J. T., "Internalized gap junctions are degraded by autophagy" 8 : 794-811, 2012

15 Takahata, K., "Growth inhibition of capsaicin on HeLa cells is not mediated by intracellular calcium mobilization" 64 : 165-171, 1999

16 Xia, X., "Glucocorticoid-induced autophagy in osteocytes" 25 : 2479-2488, 2010

17 Molitoris, J. K., "Glucocorticoid elevation of dexamethasone-induced gene 2(Dig2/ RTP801/REDD1)protein mediates autophagy in lymphocytes" 286 : 30181-30189, 2011

18 Jia, J., "Glucocorticoid dose determines osteocyte cell fate" 25 : 3366-3376, 2011

19 Pyo, J. O., "Essential roles of Atg5 and FADD in autophagic cell death : dissection of autophagic cell death into vacuole formation and cell death" 280 : 20722-20729, 2005

20 Wu, Y. T., "Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase" 285 : 10850-10861, 2010

21 Mezey, E., "Distribution of mRNA for vanilloid receptor subtype 1(VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human" 97 : 3655-3660, 2000

22 Hwang, S. W., "Direct activation of capsaicin receptors by products of lipoxygenases : endogenous capsaicin-like substances" 97 : 6155-6160, 2000

23 Michael, G. J., "Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy" 19 : 1844-1854, 1999

24 Kim, H. Y., "Differential changes in TRPV1 expression after trigeminal sensory nerve injury" 9 : 280-288, 2008

25 Liu, H., "Degradation of regulator of calcineurin 1(RCAN1)is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways" 23 : 3383-3392, 2009

26 Biggs, J. E., "Changes in vanilloid receptor 1(TRPV1)expression following lingual nerve injury" 11 : 192-201, 2007

27 Ahn, S., "CK2-mediated TEL2 phosphorylation augments nonsense-mediated mRNA decay(NMD)by increase of SMG1 stability" 1829 : 1047-1055, 2013

28 Sugiura, T., "Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1" 88 : 544-548, 2002

29 Mathew, R., "Autophagy suppresses tumorigenesis through elimination of p62" 137 : 1062-1075, 2009

30 Bejarano, E., "Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner" 23 : 2156-2169, 2012

31 Mizushima, N., "Autophagy : renovation of cells and tissues" 147 : 728-741, 2011

32 Lichtenstein, A., "Autophagy : a pathway that contributes to connexin degradation" 124 : 910-920, 2011

33 Ross, R. A., "Anandamide and vanilloid TRPV1 receptors" 140 : 790-801, 2003

34 Kedei, N., "Analysis of the native quarternary structure of vanilloid receptor 1" 276 : 28613-28619, 2001