Abstract
Transient receptor potential channels have been put forward as regulators of insulin secretion. A role for the TRPV1 ion channel in insulin secretion has been suggested in pancreatic beta cell lines. We explored whether TRPV1 is functionally expressed in RINm5F and primary beta cells from neonate and adult rats. We examined if capsaicin could activate cationic non-selective currents. Our results show that TRPV1 channels are not functional in insulin-secreting cells, since capsaicin did not produce current activation, not even under culture conditions known to induce the expression of other ion channels in these cells. Although TRPV1 channels seem to be irrelevant for the physiology of isolated beta cells, they may play a role in glucose homeostasis acting through the nerve fibers that regulate islet function. At the physiological level, we observed that Trpv1 −/− mice presented lower fasting insulin levels than their wild-type littermates, however, we did not find differences between these experimental groups nor in the glucose tolerance test or in the insulin secretion. However, we did find that the Trpv1 −/− mice exhibited a higher insulin sensitivity compared to their wild-type counterparts. Our results demonstrate that TRPV1 does not contribute to glucose-induced insulin secretion in beta cells as was previously thought, but it is possible that it may control insulin sensitivity.
Similar content being viewed by others
References
Abdul-Hay SO, Kang D, McBride M, Li L, Zhao J, Leissring MA (2011) Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS One 6:e20818
Ahern GP (2013) Transient receptor potential channels and energy homeostasis. Trends Endocrinol Metab 24:554–560
Akiba Y, Kato S, Katsube K, Nakamura M, Takeuchi K, Ishii H, Hibi T (2004) Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet beta cells modulates insulin secretion in rats. Biochem Biophys Res Commun 321:219–225
Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F, Muzzin P (2005) The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes 54:3490–3495
Bostrom M, Nie Z, Goertz G, Henriksson J, Wallberg-Henriksson H (1989) Indirect effect of catecholamines on development of insulin resistance in skeletal muscle from diabetic rats. Diabetes 38:906–910
Cao DS, Zhong L, Hsieh TH, Abooj M, Bishnoi M, Hughes L, Premkumar LS (2012) Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells. PLoS One 7:e38005
Castillo E, Lopez-Gonzalez I, De Regil-Hernandez R, Reyes-Duarte D, Sanchez-Herrera D, Lopez-Munguia A, Darszon A (2007) Enzymatic synthesis of capsaicin analogs and their effect on the T-type Ca2+ channels. Biochem Biophys Res Commun 356:424–430
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313
Cherrington AD (2005) The role of hepatic insulin receptors in the regulation of glucose production. J Clin Invest 115:1136–1139
Colsoul B, Schraenen A, Lemaire K, Quintens R, Van Lommel L, Segal A, Owsianik G, Talavera K, Voets T, Margolskee RF, Kokrashvili Z, Gilon P, Nilius B, Schuit FC, Vennekens R (2010) Loss of high-frequency glucose-induced Ca2+ oscillations in pancreatic islets correlates with impaired glucose tolerance in Trpm5−/− mice. Proc Natl Acad Sci USA 107:5208–5213
Diaz-Garcia CM, Fuentes-Silva D, Sanchez-Soto C, Dominguez-Perez D, Garcia-Delgado N, Varela C, Mendoza-Hernandez G, Rodriguez-Romero A, Castaneda O, Hiriart M (2012) Toxins from Physalia physalis (Cnidaria) raise the intracellular Ca(2+) of beta-cells and promote insulin secretion. Curr Med Chem 19:5414–5423
Diaz-Garcia CM, Sanchez-Soto C, Hiriart M (2013) TRPM channels phosphorylation as a potential bridge between old signals and novel regulatory mechanisms of insulin secretion. Curr Diabetes Rev 9:117–125
Docherty RJ, Yeats JC, Piper AS (1997) Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br J Pharmacol 121:1461–1467
Fujita S, Bohland M, Sanchez-Watts G, Watts AG, Donovan CM (2007) Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons. Am J Physiol Endocrinol Metab 293:E96–E101
Gao H, Miyata K, Bhaskaran MD, Derbenev AV, Zsombok A (2012) Transient receptor potential vanilloid type 1-dependent regulation of liver-related neurons in the paraventricular nucleus of the hypothalamus diminished in the type 1 diabetic mouse. Diabetes 61:1381–1390
Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, Lesnikov VA, Gavva NR, Romanovsky AA (2011) Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 31:1721–1733
Goswami C, Rademacher N, Smalla KH, Kalscheuer V, Ropers HH, Gundelfinger ED, Hucho T (2010) TRPV1 acts as a synaptic protein and regulates vesicle recycling. J Cell Sci 123:2045–2057
Gram DX, Ahren B, Nagy I, Olsen UB, Brand CL, Sundler F, Tabanera R, Svendsen O, Carr RD, Santha P, Wierup N, Hansen AJ (2007) Capsaicin-sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes. Eur J Neurosci 25:213–223
Hail N Jr (2003) Mechanisms of vanilloid-induced apoptosis. Apoptosis 8:251–262
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflug Arch 391:85–100
Hiriart M, Aguilar-Bryan L (2008) Channel regulation of glucose sensing in the pancreatic beta-cell. Am J Physiol Endocrinol Metab 295:E1298–E1306
Hiriart M, Ramirez-Medeles MC (1991) Functional subpopulations of individual pancreatic B-cells in culture. Endocrinology 128:3193–3198
Islam MS (2011) TRP channels of islets. Adv Exp Med Biol 704:811–830
Jabin Fagelskiold A, Kannisto K, Bostrom A, Hadrovic B, Farre C, Eweida M, Wester K, Islam MS (2012) Insulin-secreting INS-1E cells express functional TRPV1 channels. Islets 4:1–8
Jara-Oseguera A, Simon SA, Rosenbaum T (2008) TRPV1: on the road to pain relief. Curr Mol Pharmacol 1:255–269
Jermendy A, Toschi E, Aye T, Koh A, Aguayo-Mazzucato C, Sharma A, Weir GC, Sgroi D, Bonner-Weir S (2011) Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells. Diabetologia 54:594–604
Latham AN (1978) Effect of data transformation on t-test sensitivity. Br J Clin Pharmacol 6:535–537
Liang Y, Osborne MC, Monia BP, Bhanot S, Gaarde WA, Reed C, She P, Jetton TL, Demarest KT (2004) Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 53:410–417
Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z (2012) TRPV1 activation improves exercise endurance and energy metabolism through PGC-1alpha upregulation in mice. Cell Res 22:551–564
Marshall NJ, Liang L, Bodkin J, Dessapt-Baradez C, Nandi M, Collot-Teixeira S, Smillie SJ, Lalgi K, Fernandes ES, Gnudi L, Brain SD (2012) A role for TRPV1 in influencing the onset of cardiovascular disease in obesity. Hypertension 61:246–252
McCoy DD, Zhou L, Nguyen AK, Watts AG, Donovan CM, McKemy DD (2013) Enhanced insulin clearance in mice lacking TRPM8 channels. Am J Physiol Endocrinol Metab 305:E78–E88
Mergler S, Skrzypski M, Sassek M, Pietrzak P, Pucci C, Wiedenmann B, Strowski MZ (2012) Thermo-sensitive transient receptor potential vanilloid channel-1 regulates intracellular calcium and triggers chromogranin A secretion in pancreatic neuroendocrine BON-1 tumor cells. Cell Signal 24:233–246
Mogi C, Nakakura T, Okajima F (2013) Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic beta-cell functions. Endocr J 53:789–795
Morales-Lazaro SL, Simon SA, Rosenbaum T (2013) The role of endogenous molecules in modulating pain through TRPV1. J Physiol 591:3109–3121
Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A (2004) Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 279:25665–25672
Navarro-Tableros V, Fiordelisio T, Hernandez-Cruz A, Hiriart M (2007a) Nerve growth factor promotes development of glucose-induced insulin secretion in rat neonate pancreatic beta cells by modulating calcium channels. Channels (Austin) 1:408–416
Navarro-Tableros V, Fiordelisio T, Hernandez-Cruz A, Hiriart M (2007b) Physiological development of insulin secretion, calcium channels, and GLUT2 expression of pancreatic rat beta-cells. Am J Physiol Endocrinol Metab 292:E1018–E1029
Neher E (1992) Nobel lecture. Ion channels for communication between and within cells. EMBO J 11:1672–1679
Neill JD, Frawley LS (1983) Detection of hormone release from individual cells in mixed populations using a reverse hemolytic plaque assay. Endocrinology 112:1135–1137
Nieto-Posadas A, Jara-Oseguera A, Rosenbaum T (2011) TRP channel gating physiology. Curr Top Med Chem 11:2131–2150
Nieto-Posadas A, Picazo-Juarez G, Llorente I, Jara-Oseguera A, Morales-Lazaro S, Escalante-Alcalde D, Islas LD, Rosenbaum T (2012) Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat Chem Biol 8:78–85
Osborne JW (2010). Improving your data transformations: applying the Box-Cox transformation, (ed)^(eds) Practical Assessment, Research & Evaluation, 1–8. Available online: http://pareonline.net/getvn.asp?v=15&n=12
Pabbidi RM, Yu SQ, Peng S, Khardori R, Pauza ME, Premkumar LS (2008) Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol Pain 4:9
Polak M, Scharfmann R, Seilheimer B, Eisenbarth G, Dressler D, Verma IM, Potter H (1993) Nerve growth factor induces neuron-like differentiation of an insulin-secreting pancreatic beta cell line. Proc Natl Acad Sci USA 90:5781–5785
Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, Tsui H, Tang L, Tsai S, Santamaria P, Driver JP, Serreze D, Salter MW, Dosch HM (2006) TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 127:1123–1135
Rosenbaum T, Vidaltamayo R, Sanchez-Soto MC, Zentella A, Hiriart M (1998) Pancreatic beta cells synthesize and secrete nerve growth factor. Proc Natl Acad Sci USA 95:7784–7788
Rubenstein AH, Spitz I (1968) Role of the kidney in insulin metabolism and excretion. Diabetes 17:161–169
Sanz-Salvador L, Andres-Borderia A, Ferrer-Montiel A, Planells-Cases R (2012) Agonist- and Ca2+-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation. J Biol Chem 287:19462–19471
Schumacher MA, Moff I, Sudanagunta SP, Levine JD (2000) Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem 275:2756–2762
Stein AT, Ufret-Vincenty CA, Hua L, Santana LF, Gordon SE (2006) Phosphoinositide 3-kinase binds to TRPV1 and mediates NGF-stimulated TRPV1 trafficking to the plasma membrane. J Gen Physiol 128:509–522
Tanaka H, Shimaya A, Kiso T, Kuramochi T, Shimokawa T, Shibasaki M (2011) Enhanced insulin secretion and sensitization in diabetic mice on chronic treatment with a transient receptor potential vanilloid 1 antagonist. Life Sci 88:559–563
Taylor AC, McCarthy JJ, Stocker SD (2008) Mice lacking the transient receptor vanilloid potential 1 channel display normal thirst responses and central Fos activation to hypernatremia. Am J Physiol Regul Integr Comp Physiol 294:R1285–R1293
Touska F, Marsakova L, Teisinger J, Vlachova V (2011) A “cute” desensitization of TRPV1. Curr Pharm Biotechnol 12:122–129
Uchida K, Dezaki K, Damdindorj B, Inada H, Shiuchi T, Mori Y, Yada T, Minokoshi Y, Tominaga M (2011) Lack of TRPM2 impaired insulin secretion and glucose metabolisms in mice. Diabetes 60:119–126
Vidaltamayo R, Sanchez-Soto MC, Hiriart M (2002) Nerve growth factor increases sodium channel expression in pancreatic beta cells: implications for insulin secretion. FASEB J 16:891–892
Vos MH, Neelands TR, McDonald HA, Choi W, Kroeger PE, Puttfarcken PS, Faltynek CR, Moreland RB, Han P (2006) TRPV1b overexpression negatively regulates TRPV1 responsiveness to capsaicin, heat and low pH in HEK293 cells. J Neurochem 99:1088–1102
Waluk DP, Vielfort K, Derakhshan S, Aro H, Hunt MC (2012) N-acyl taurines trigger insulin secretion by increasing calcium flux in pancreatic beta-cells. Biochem Biophys Res Commun 430:54–59
Wang C, Hu HZ, Colton CK, Wood JD, Zhu MX (2004) An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels. J Biol Chem 279:37423–37430
Wang P, Yan Z, Zhong J, Chen J, Ni Y, Li L, Ma L, Zhao Z, Liu D, Zhu Z (2012) Transient receptor potential vanilloid 1 activation enhances gut glucagon-like peptide-1 secretion and improves glucose homeostasis. Diabetes 61:2155–2165
Wang F, Gao H, Kubo H, Fan X, Zhang H, Berretta R, Chen X, Sharp T, Starosta T, Makarewich C, Li Y, Molkentin JD, Houser SR (2013) T-type Ca(2)(+) channels regulate the exit of cardiac myocytes from the cell cycle after birth. J Mol Cell Cardiol 62:122–130
Wanner SP, Garami A, Romanovsky AA (2011) Hyperactive when young, hypoactive and overweight when aged: connecting the dots in the story about locomotor activity, body mass, and aging in Trpv1 knockout mice. Aging (Albany NY) 3:450–454
Yang RG, Xi N, Lai KW, Zhong BH, Fung CK, Qu CG, Wang DH (2011) Nanomechanical analysis of insulinoma cells after glucose and capsaicin stimulation using atomic force microscopy. Acta Pharmacol Sin 32:853–860
Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M (2007) Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res 100:1063–1070
Zhang Z, Zhang W, Jung DY, Ko HJ, Lee Y, Friedline RH, Lee E, Jun J, Ma Z, Kim F, Tsitsilianos N, Chapman K, Morrison A, Cooper MP, Miller BA, Kim JK (2012) TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab 302:E807–E816
Zsiros E, Kis-Toth K, Hajdu P, Gaspar R, Bielanska J, Felipe A, Rajnavolgyi E, Panyi G (2009) Developmental switch of the expression of ion channels in human dendritic cells. J Immunol 183:4483–4492
Acknowledgments
We are grateful to Dr. Clara Ortega for providing the RINm5F cells. To Ana María Escalante-Gonzalbo and Francisco Pérez-Eugenio, from the Computer Unit, and to Dr. Fernando García from the Microscopy Unit for excellent technical support. Also to Dr. Claudia Rivera-Cerecedo, Dr. Héctor Malagón and the bioterium staff. All from Instituto de Fisiología Celular, UNAM. Work in Dr. Hiriart laboratory was supported by grants from Consejo Nacional de Ciencia y Tecnología CONACYT CB2009-131647, and DGAPA-PAPIIT IN215611, Universidad Nacional Autónoma de México (UNAM). C. M. Diaz-Garcia is a PhD student from Posgrado en Ciencias Biológicas, UNAM and was supported by a doctoral fellowship from CONACyT. Work in Dr. Rosenbaum laboratory was supported by grants from the Marcos Moshinsky Foundation, CONACyT 129474, DGAPA-PAPIIT IN204111 and IN200314. S. L. Morales-Lázaro is supported by the postdoctoral scholarship program of UNAM (DGAPA).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Diaz-Garcia, C.M., Morales-Lázaro, S.L., Sánchez-Soto, C. et al. Role for the TRPV1 Channel in Insulin Secretion from Pancreatic Beta Cells. J Membrane Biol 247, 479–491 (2014). https://doi.org/10.1007/s00232-014-9658-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-014-9658-8