Jonathon Willets

Biography

Senior Lecturer, Department of Cancer Studies and Molecular Medicine

Department: Molecular and Cell Biology
Telephone: 0116 229 7148
Emailjmw23@le.ac.uk
Web Links: https://www2.le.ac.uk/departments/molcellbiol

Personal Details

  • Post-Doctoral Research Assistant, University of Leicester, Department of Anaesthesia, Leicester Royal Infirmary (1995-1996)
  • Post-Doctoral Research Associate, Department of Pharmacology, University of Bristol (1996-1999)
  • Post-Doctoral Research Associate, Department of Cell Physiology and Pharmacology, University of Leicester (1999-2005)
  • Lecturer in Reproductive Sciences, Department of Cancer Studies and Molecular Medicine, University of Leicester (2006-2011)
  • Senior Lecturer, Department of Cancer Studies and Molecular Medicine, University of Leicester (2011-2014)
  • Associate Professor, Department of Molecular & Cell Biology , University of Leicester (2014-)

Qualifications

  • BSc in Applied Biochemistry (with Industrial Placement at ICI Pharmaceuticals), Liverpool John Moores University (1987-1991)
  • PhD Pharmacology and Toxicology, Division of Chemical Pathology, Centre for Mechanisms in Human Toxicity, and Department of Anaesthesia, University of Leicester (1992-1995)
  • Fellow of the Higher Education Academy (2016)

Teaching

  • Physiology
  • Pharmacology
  • Endocrinology

Publications

  1. Pearce A, Sanders L, Brighton PJ, Rana S, Konje JC, Willets JM. Reciprocal regulation of b2- adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin3. Cell Signal (2017);38:182-191.
  2. Willets JM, Nash CA, Rainbow RD, Nelson CP, Challiss RA. Defining the roles of arrestin2 and arrestin3 in vasoconstrictor receptor desensitization in hypertension. Am J Physiol Cell Physiol (2015); 309:C179-189.
  3. Willets JM, Brighton PJ, Windell LN, Rana S, Nash CA, Konje JC. Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins. Mol Cell Endocrinol (2015);407:57-66.
  4. Brignell JL, Perry MD, Nelson CP, Willets JM, Challiss RA, Davies NW. Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B. PLoS One (2015);10:e0121285.
  5. Ayakannu T, Taylor AH, Willets JM, Konje JC. The evolving role of the endocannabinoid system in gynaecological cancer. Hum Reprod Update (2015);21:517-535.
  6. Ayakannu T, Taylor AH, Willets JM, Brown L, Lambert DG, McDonald J, Davies Q, Moss EL, Konje JC. Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma. Mol Hum Reprod (2015);21:723-735.
  7. Ayakannu T, Taylor A, Willets J, Marczylo T, Brown L, Davies Q, Moss E, Konje J. Effect of anandamide on endometrial adenocarcinoma (Ishikawa) cell numbers: implications for endometrial cancer therapy. Lancet (2015);385 Suppl 1:S20.
  8. Gebeh AK, Willets JM, Marczylo TH, Konje JC. Plasma anandamide and related n-acylethanolamide levels are not elevated in pregnancies complicated by hyperemesis gravidarum. J Matern Fetal Neonatal Med (2014);27:954-959.
  9. Bakali E, Elliott RA, Taylor AH, Lambert DG, Willets JM, Tincello DG. Human urothelial cell lines as potential models for studying cannabinoid and excitatory receptor interactions in the urinary bladder. Naunyn Schmiedebergs Arch Pharmacol (2014);387:581-589.
  10. Amoako AA, Marczylo TH, Elson J, Taylor AH, Willets JM, Konje JC. Relationship between seminal plasma levels of anandamide congeners palmitoylethanolamide and oleoylethanolamide and semen quality. Fertil Steril (2014);102:1260-1267.
  11. Gebeh AK, Willets JM, Bari M, Hirst RA, Marczylo TH, Taylor AH, Maccarrone M, Konje JC. Elevated anandamide and related N-acylethanolamine levels occur in the peripheral blood of women with ectopic pregnancy and are mirrored by changes in peripheral fatty acid amide hydrolase activity. J Clin Endocrinol Metab (2013);98:1226-1234.
  12. Bakali E, Elliott RA, Taylor AH, Willets J, Konje JC, Tincello DG. Distribution and function of the endocannabinoid system in the rat and human bladder. Int Urogynecol J (2013);24:855-863.
  13. Ayakannu T, Taylor AH, Marczylo TH, Willets JM, Konje JC. The endocannabinoid system and sex steroid hormone-dependent cancers. Int J Endocrinol (2013);2013:259676.
  14. Amoako AA, Marczylo TH, Marczylo EL, Elson J, Willets JM, Taylor AH, Konje JC. Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Hum Reprod (2013);28:2058-2066.
  15. Amoako AA, Gebeh AK, Marczylo EL, Willets JM, Elson J, Marczylo TH, Konje JC. Impact of reference gene selection for type 2 cannabinoid receptor gene expression studies in human spermatozoa. Andrologia (2013);45:278-284.
  16. Morris GE, Nelson CP, Brighton PJ, Standen NB, Challiss RA, Willets JM. Arrestins 2 and 3 differentially regulate ETA and P2Y2 receptor-mediated cell signaling and migration in arterial smooth muscle. Am J Physiol Cell Physiol (2012);302:C723-734.
  17. Gebeh AK, Willets JM, Marczylo EL, Taylor AH, Konje JC. Ectopic pregnancy is associated with high anandamide levels and aberrant expression of FAAH and CB1 in fallopian tubes. J Clin Endocrinol Metab (2012);97:2827-2835.
  18. Gebeh AK, Marczylo EL, Amoako AA, Willets JM, Konje JC. Variation in stability of endogenous reference genes in fallopian tubes and endometrium from healthy and ectopic pregnant women. Int J Mol Sci (2012);13:2810-2826.
  19. Willets JM. Approaches to study GPCR regulation in native systems. Methods Mol Biol (2011);746:99-112.
  20. Nelson CP, Rainbow RD, Brignell JL, Perry MD, Willets JM, Davies NW, Standen NB, Challiss RA. Principal role of adenylyl cyclase 6 in K+ channel regulation and vasodilator signalling in vascular smooth muscle cells. Cardiovasc Res (2011);91:694-702.
  21. Morris GE, Nelson CP, Everitt D, Brighton PJ, Standen NB, Challiss RA, Willets JM. G protein-coupled receptor kinase 2 and arrestin2 regulate arterial smooth muscle P2Y-purinoceptor signalling. Cardiovasc Res (2011);89:193-203.
  22. Engemise SL, Willets JM, Taylor AH, Emembolu JO, Konje JC. Changes in glandular and stromal estrogen and progesterone receptor isoform expression in eutopic and ectopic endometrium following treatment with the levonorgestrel-releasing intrauterine system. Eur J Obstet Gynecol Reprod Biol (2011);157:101-106.
  23. Engemise SL, Willets JM, Emembolu JO, Konje JC. The effect of the levonorgestrel-releasing intrauterine system, Mirena(R) on mast cell numbers in women with endometriosis undergoing symptomatic treatment. Eur J Obstet Gynecol Reprod Biol (2011);159:439-442.
  24. Brighton PJ, Rana S, Challiss RJ, Konje JC, Willets JM. Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells. Br J Pharmacol (2011);162:1603-1617.
  25. Brighton PJ, Marczylo TH, Rana S, Konje JC, Willets JM. Characterization of the endocannabinoid system, CB1 receptor signalling and desensitization in human myometrium. Br J Pharmacol (2011);164:1479-1494.
  26. Morris GE, Nelson CP, Standen NB, Challiss RA, Willets JM. Endothelin signalling in arterial smooth muscle is tightly regulated by G protein-coupled receptor kinase 2. Cardiovasc Res (2010);85:424-433.
  27. Bambang KN, Karasu T, Gebeh A, Taylor AH, Marczylo TH, Lam P, Willets JM, Konje JC. From Fertilisation to Implantation in Mammalian Pregnancy-Modulation of Early Human Reproduction by the Endocannabinoid System. Pharmaceuticals (Basel) (2010);3:2910-2929.
  28. Amoako AA, Marczylo TH, Lam PM, Willets JM, Derry A, Elson J, Konje JC. Quantitative analysis of anandamide and related acylethanolamides in human seminal plasma by ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci (2010);878:3231-3237.
  29. Willets JM, Brighton PJ, Mistry R, Morris GE, Konje JC, Challiss RA. Regulation of oxytocin receptor responsiveness by G protein-coupled receptor kinase 6 in human myometrial smooth muscle. Mol Endocrinol (2009);23:1272-1280.
  30. Brighton PJ, McDonald J, Taylor AH, Challiss RA, Lambert DG, Konje JC, Willets JM. Characterization of anandamide-stimulated cannabinoid receptor signaling in human ULTR myometrial smooth muscle cells. Mol Endocrinol (2009);23:1415-1427.
  31. Willets JM, Taylor AH, Shaw H, Konje JC, Challiss RA. Selective regulation of H1 histamine receptor signaling by G protein-coupled receptor kinase 2 in uterine smooth muscle cells. Mol Endocrinol (2008);22:1893-1907
  32. Nelson CP, Willets JM, Davies NW, Challiss RA, Standen NB. Visualizing the temporal effects of vasoconstrictors on PKC translocation and Ca2+ signaling in single resistance arterial smooth muscle cells. Am J Physiol Cell Physiol (2008);295:C1590-1601.
  33. Willets JM, Nelson CP, Nahorski SR, Challiss RA. The regulation of M1 muscarinic acetylcholine receptor desensitization by synaptic activity in cultured hippocampal neurons. J Neurochem (2007);103:2268-2280.
  34. Dowling MR, Willets JM, Budd DC, Charlton SJ, Nahorski SR, Challiss RA. A single point mutation (N514Y) in the human M3 muscarinic acetylcholine receptor reveals differences in the properties of antagonists: evidence for differential inverse agonism. J Pharmacol Exp Ther (2006);317:1134-1142.
  35. Young KW, Billups D, Nelson CP, Johnston N, Willets JM, Schell MJ, Challiss RA, Nahorski SR. Muscarinic acetylcholine receptor activation enhances hippocampal neuron excitability and potentiates synaptically evoked Ca2+ signals via phosphatidylinositol 4,5-bisphosphate depletion. Mol Cell Neurosci (2005);30:48-57.
  36. Willets JM, Nahorski SR, Challiss RA. Roles of phosphorylation-dependent and -independent mechanisms in the regulation of M1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 in hippocampal neurons. J Biol Chem (2005);280:18950-18958.
  37. Willets JM, Nash MS, Challiss RA, Nahorski SR. Imaging of muscarinic acetylcholine receptor signaling in hippocampal neurons: evidence for phosphorylation-dependent and -independent regulation by G-protein-coupled receptor kinases. J Neurosci (2004);24:4157-4162.
  38. Nash MS, Willets JM, Billups B, John Challiss RA, Nahorski SR. Synaptic activity augments muscarinic acetylcholine receptor-stimulated inositol 1,4,5-trisphosphate production to facilitate Ca2+ release in hippocampal neurons. J Biol Chem (2004);279:49036-49044.
  39. Young KW, Willets JM, Parkinson MJ, Bartlett P, Spiegel S, Nahorski SR, Challiss RA. Ca2+/calmodulin-dependent translocation of sphingosine kinase: role in plasma membrane relocation but not activation. Cell Calcium (2003);33:119-128.
  40. Willets JM, Mistry R, Nahorski SR, Challiss RA. Specificity of G protein-coupled receptor kinase 6-mediated phosphorylation and regulation of single-cell M3 muscarinic acetylcholine receptor signaling. Mol Pharmacol (2003);64:1059-1068.
  41. Willets JM, Challiss RA, Nahorski SR. Non-visual GRKs: are we seeing the whole picture? Trends Pharmacol Sci (2003);24:626-633.
  42. Ghadessy RS, Willets JM, Kelly E. G protein-coupled receptor kinase 6 (GRK6) selectively regulates endogenous secretin receptor responsiveness in NG108-15 cells. Br J Pharmacol (2003);138:660-670.
  43. Willets JM, Challiss RA, Nahorski SR. Endogenous G protein-coupled receptor kinase 6 Regulates M3 muscarinic acetylcholine receptor phosphorylation and desensitization in human SH-SY5Y neuroblastoma cells. J Biol Chem (2002);277:15523-15529.
  44. Willets JM, Challiss RA, Kelly E, Nahorski SR. G protein-coupled receptor kinases 3 and 6 use different pathways to desensitize the endogenous M3 muscarinic acetylcholine receptor in human SH-SY5Y cells. Mol Pharmacol (2001);60:321-330.
  45. Willets J, Kelly E. Desensitization of endogenously expressed d-opioid receptors: no evidence for involvement of G protein-coupled receptor kinase 2. Eur J Pharmacol (2001);431:133-141.
  46. Willets JM, Parent JL, Benovic JL, Kelly E. Selective reduction in A2 adenosine receptor desensitization following antisense-induced suppression of G protein-coupled receptor kinase 2 expression. J Neurochem (1999);73:1781-1789.
  47. Mundell SJ, Luty JS, Willets J, Benovic JL, Kelly E. Enhanced expression of G protein-coupled receptor kinase 2 selectively increases the sensitivity of A2A adenosine receptors to agonist-induced desensitization. Br J Pharmacol (1998);125:347-356.
  48. Willets JM, Lambert DG, Lunec J, Griffiths HR, Phillipson O. Neurotoxicity of 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) and effects on catecholamine homeostasis in SH-SY5Y cells. Environ Toxicol Pharmacol (1996);2:59-68.
  49. Lambert DG, Willets JM, Atcheson R, Frost C, Smart D, Rowbotham DJ, Smith G. Effects of propofol and thiopentone on potassium- and carbachol-evoked [3H]noradrenaline release and increased [Ca2+]i from SH-SY5Y human neuroblastoma cells. Biochem Pharmacol (1996);51:1613-1621.
  50. Willets JM, Lambert DG, Lunec J, Griffiths HR. Studies on the neurotoxicity of 6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (salsolinol) in SH-SY5Y cells. Eur J Pharmacol (1995);293:319-326.
  51. Willets JM, Lunec J, Williams AC, Griffiths HR. Neurotoxicity of nicotinamide derivatives: their role in the aetiology of Parkinson's disease. Biochem Soc Trans (1993);21 ( Pt 3):299
  52. Willets JM, Lambert DG, Griffiths HR. Suitability of B65 and SH-SY5Y neuroblastoma cells as models for 'in vitro' neurotoxicity testing. Biochem Soc Trans (1993);21:452S.
  53. Wright JA, Marsden AM, Willets JM, Orton TC. Hepatocarcinogenic effect of vinyl carbamate in the C57Bl/10J strain mouse. Toxicol Pathol (1991);19:258-265.

Research

I have interests in all forms of receptor regulation however my work is primarily concerned with the role of G protein-coupled receptor kinases (GRKs) in the regulation of endogenously expressed G protein-coupled receptors (GPCRs). Current work is focused on identifying the molecular mechanisms underlying GPCR regulation of smooth muscle excitability in arterial and uterine smooth muscle with relevance to hypertension and pre- term labour, respectively.

Hypertension is an important risk factor in the development of major cardiac, cerebral and renal diseases. A hyper-contractility of blood vessels contributes to the hypertensive phenotype and present pharmacological approaches to combating hypertension focus, directly or indirectly, on the GPCRs within vascular smooth muscle that regulate the diameter of blood vessels. Activation of the phospholipase C (PLC) pathway in arterial smooth muscle by a diverse array of contractile ligands (e.g. endothelin, angiotensin II, noradrenalin, extracellular nucleotides) increases intracellular Ca2+, which is of cardinal importance to their vasoconstrictor activity. Activation of phospholipase C signalling can also effect a number of downstream signalling pathways, including extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (p38 MAPK), which have been implicated in vascular smooth muscle hypertrophy, hyperplasia inflammatory responses and fibrosis, leading to hypertension and vascular remodelling. We are currently investigating the roles that GRK and arrestin proteins play in the regulation of these signalling pathways to uncover their ability to regulate hypertensive disorders.

Endocannabinoids (endogenous cannabis-like compounds) have potent effects upon human reproduction. Indeed, the localised concentration of the endocannabinoid anandamide is a determinant of where a fertilised embryo will implant in the myometrium. This appears to be linked to the local expression of the enzyme that degrades anandamide fatty acid amide hydrolase (FAAH). Furthermore, low expression, and or inactivity of FAAH, combined with raised circulating levels of anandamide appears linked to implantation failure and spontaneous abortion, preterm labour and foetal growth problems. The effects of anandamide are regulated through the action of CB1 and CB2 receptors, both of which are expressed in reproductive tissues. My interests are in determining the regulatory pathways associated with CB signalling in myometrium and its importance in pre-term labour and foetal growth problems.

Uterine contractility is mediated through the action of hormone receptors (e.g. oxytocin, b2-adrenoceptor, prostaglandins, endothelin, angiotensin II). During pregnancy these receptors are tightly controlled, to prevent contraction and pre- term labour. The molecular processes involved are not fully understood but are likely to involve desensitization and down-regulation of receptors. The initial stages in this process usually require GRK-mediated phosphorylation of the agonist-occupied receptor, prior to binding of arrestin proteins, which both physically inhibit the interaction of receptor and G-protein, and promote receptor internalisation.

Supervision

  • Hypertension
  • Vascular remodeling
  • Atherosclerosis

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Department of Molecular and Cell Biology

T: +44(0)116 229 7038
E: MolCellBiol@le.ac.uk

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