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Trpv3 Is a Polymodal Receptor

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Trpv3 Is a Polymodal Receptor TRPV3 IS A POLYMODAL RECEPTOR DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Graduate School of the Ohio State University By Craig K. Colton, B.S. The Ohio State University 2006 Dissertation Committee: Approved by Dr. Michael X Zhu, Adviser Dr. Tsonwin Hai Adviser Dr. John Oberdick Ohio State Biochemistry Graduate Program Dr. Chien-liang Glenn Lin Dr. Thomas Kasulis ABSTRACT The vanilloid family of transient receptor potential (TRPV) channels contains four thermosensitive members (TRPV1-4), each having a distinguishable temperature threshold (Th). In addition to thermal stimuli, TRPV1, or capsaicin receptor, has been shown to respond to acidic pH, exogenous ligands (capsaicin and resiniferatoxin), and endogenous substances such as anandamide and lipooxygenase products. Furthermore, TRPV1 channel activity is modulated by G-protein coupled receptors (GPCRs) such as bradykinin (Bk) and purinergic (P2Y) receptors. The polymodal nature of TRPV1 has resulted in the identification of its role in thermal sensation, pain, asthma, urinary incontinence, muscle cramps, and migraine headaches. TRPV3 is the newest member of the thermosensitive TRPV channels. Although TRPV3 has been shown to respond to warm temperatures, it was reported to be unresponsive to low pH and chemical activators of other TRPV family members. Our data shows that TRPV3 is activated by the boron containing compound, 2APB. In addition, we report here that TRPV3 responds to pH 5.6 when overexpressed in HEK293 cells, and that this response is sensitive to PKA. Also, TRPV3 channel activity is modulated by GPCRs such as bradykinin (B2R), histamine (H1R), and purinergic receptors. We also show that the activation of TRPV3 by the B2R is dependant on phospholipase C, arachidonic acid (AA), and depletion of phosphatidylinositol 4,5-bisphosphate from the plasma membrane. Interestingly, we ii show that several other lipid, or lipid-like compounds, modulate TRPV3 channel activity. We also present evidence that TRPV3 is capable of forming heterotetramers with TRPV1. The similarities in the properties of TRPV3 and TRPV1, as well as the ability of TRPV3 to form heterotetramers with TRPV1, suggests that TRPV3 may be involved in many of the same physiological processes as TRPV1. We therefore conclude that TRPV3 is a polymodal receptor, capable of responding to thermal stimuli, GPCRs, acidic pH, as well as lipid or lipid-like agonists, and may be involved in physiological processes similar to TRPV1. iii Dedicated to my parents and sister iv ACKNOWLEDGMENTS I am greatly indebted to my adviser, Mike X. Zhu, for constant guidance, support, encouragement and patients throughout my time in his lab. I would like to thank my General Exam committee members, Dr. Tsonwin Hai, Dr. John Oberdick, Dr. Arthur Strauch III and Dr. Mike Zhu. I would like to thank my Dissertation committee members, Dr. Tsonwin Hai, Dr. John Oberdick, Dr. Glenn Lin and Dr. Mike Zhu for their efforts in supporting me through my general exam. I am particularly appreciative of the efforts by Dr. Hong-Zhen Hu and Rui Xiao for the electrophysiological support of my experiments. I feel privileged to have worked with Chumbo Wang, Hong-Zhen Hu, Rui Xiao and Jisen Tang and Dina Zhu. Finally, I could not have completed my research without the support of my friends and family. v VITA July 11, 1971……………………………...…… Born---Altuna, Pennsylvania 1989…………………………………………… Graduate high school Girard High School 1989-1992……………………………………… United States Army 1992-present…………………………………… Ohio Army National Guard 1993-1998……………………………………… B.S. Biochemistry B.S. Microbiology The Ohio State University 2001…………………………………………… Graduate of Officers Candidate School, Army 2004-2005……………………………………… United States Army Deployed to Kosovo 2005…………………………………………… Ohio National Guard Deployed to MS and LA in support of Hurricane Katrina relief effort PUBLICATIONS Colton C & Zhu MX. (2006) 2APB activates TRPV1, TRPV2 and TRPV3. Handbook of Experimental Pharmacology, in press Xiao R, Tang J, Wang C, Colton CK, Tian J, Zhu MX. (2006) Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations. Journal of General Physiology, in revision. Hu HZ, Xiao R, Wang C, Gao N, Colton CK, Wood JD, Zhu MX. (2006) Potentiation of TRPV3 channel function by unsaturated fatty acids. J Cell Physiol. 208(1): 201-12. Hu HZ, Gu Q, Wang C, Colton CK, Tang J, Kinoshita-Kawada M, Lee LY, Wood JD, Zhu MX (2004) 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J Biol Chem. 279(34): 35741-8. 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(36): 37423-30. vi Nguyen KT, Hu X, Colton C, Chakrabarti R, Zhu MX, Pei D. (2003) Characterization of a human peptide deformylase: implications for antibacterial drug design. Biochemistry. 42(33): 9952-8. FIELDS OF STUDY Major Fields: Biochemistry Neuroscience Molecular Biology Calcium fluorometric techniques vii TABLE OF CONTENTS Page Abstract……………………………………………………………………………… ii Dedication…………………………………………………………………………… iv Acknowledgments……………………………………………………………...….. v Vita…………………………………………………………………………………. vi List of Tables……………………………………………………………………..... xii List of Figures……………………………………………………………………… xiii Abbreviations………………………………………………………………..……. xvii Chapters: 1. Background and Significance…………………………………………………….. 1 1.1. The TRP superfamily………………………………………………….….. 1 1.2. The TRPV family and thermal responsiveness…………………………… 3 1.3. Thermal TRP channels and temperature sensation……………………….. 4 1.4. Pain management is a growing problem in our society……………….…... 5 1.5. The physiology of pain …………………………………………………… 6 1.6. TRPV1 is the classic example of a thermal and pain receptor……………. 9 1.7. Properties of TRPV3 prior to this research…………….……………….... 12 2. 2APB is a chemical activator of TRPV3……………………………………...….. 16 1.8. Introduction…………………………………………………………….…. 16 1.9. Materials and methods……………………………………………………. 19 1.9.1. DNA constructs, cell culture, and transfections……………...….. 19 1.9.2. Whole cell recordings of HEK293 cells……………………….… 21 viii 1.9.3. Intracellular Ca2+ measurements………………………………… 22 1.9.4. Membrane potential measurements…………………….….…..… 23 1.9.5. cRNA synthesis and expression in Xenopus oocytes………….… 23 1.9.6. Two-electrode voltage clamp…………………...…………….…. 24 2.3. Results………………………………………………………………......… 25 2.3.1. 2APB induces calcium influx through TRPV3 channels in a dose-dependent manner…………………………………………. 25 2.3.2. Activation of TRPV3 by 2APB is inhibited by RR…….….….… 26 2.3.3. TRPV3 is localized to the plasma membrane……………...….… 27 2.3.4. 2APB elicits membrane depolarization in TRPV3 expressing cells……………………………………………………………..... 29 2.3.5. 2APB and heat elicit similar currents in TRPV3 expressing cell... 30 2+ 2.3.6. TRPV3D641N is less sensitive to Ca -dependent inhibition than wild type TRPV3………………………………………....… 31 2.3.7. TRPV3 is sensitized to repetitive stimulation by 2APB.…..….…. 31 2.3.8. 2APB activates currents in Xenopus oocytes expressing TRPV3.. 32 2.3.9. 2APB activates TRPV1 and TRPV2 at higher concentrations.….. 33 2.4 Discussion…………………………………………………………....…….. 34 3. TRPV3 is modulated by signaling events downstream of G-Protein Coupled Receptors……………………………………………………………...…. 54 3.1. Introduction………………………………………………………………... 54 3.2. Materials and methods………………………………………...…..………. 60 3.2.1. DNA constructs, cell culture, and transfections………....……....... 60 3.2.2. For all experimental procedures, see section 2.2……...………….. 60 3.3. Results………………………………………………………………...…… 60 3.3.1. TRPV3 is activated by GPCRs of the Gq/11 pathway……………... 60 3.3.2. RR and the removal of extracellular Ca2+ reduce the 2+ Gq/11PCR induced rise in [Ca ]i through TRPV3………………... 62 3.3.3. Activation of TRPV3 by Gq/11PCRs causes membrane depolarization…………………………………………………….. 62 3.3.4. Gq/11PCRs potentiates the 2APB response of TRPV3…….………. 63 3.3.5. Signaling events downstream of G(q/11)PCRs modulate TRPV3…. 65 3.3.5.1. The effect of PKA and PKC phosphorylation on the G(q/11)PCR induced activation of TRPV3……………. 65 3.3.5.2. The effect of PLC on the G(q/11)PCR-induced activation of TRPV3…………………………………. 66 3.3.5.3. The effect of polyunsaturated fatty acids on the G(q/11)PCR-induced activation of TRPV3……...…….. 67 3.3.5.4. The effect of PIP2 depletion on the G(q/11)PCR- induced activation of TRPV3………………………... 68 3.4. Discussion………………………………………………………….………. 72 4. TRPV3 channel activity is modulated by acid…………………………….……..… 95 ix 4.1. Introduction…………………………………………………………....…… 95 4.2. Materials and methods…………………………………………………...… 98 4.2.1. DNA constructs, cell culture, and transfections………....……....... 98 4.2.2. Acidification of ECS solution for intracellular Ca2+ measurements using the Flex Station…………………………………………….. 98 4.2.3. Intracellular Ca2+ measurements using fura-2……………...…...... 99 4.2.4. For all other experimental procedures, see Section 2.2………...… 99 4.3. Results…………………………………………………………………...….. 99 2+ 4.3.1. Acid causes an increase in [Ca ]i in TRPV3D641N expressing cells at lower temperatures…………………………………………...… 99 2+ 4.3.2. The acid-induced increase in [Ca ]i in both TRPV3 and TRPV3D641N expressing cells is temperature dependent……….... 100 4.3.3. Acid activates TRPV3 on the plasma membrane……………….... 101 4.3.4. Capsaicin inhibits the acid-induced activation of TRPV3D641N…... 103 4.3.5. Acid activates currents in HEK293 cells
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