Male Reproductive Pharmacology
Likely locations on various cell types of membrane bound receptors and extracellular messengers which play a role in the control of prostatic smooth muscle contractility.
Although the development of male genitourinary organs and tissues is controlled hormonally, their physiological function is under the control of the sympathetic nervous system. This autonomic control by the sympathetic and parasympathetic nervous system has a number of consequences in male health. Specifically, overactivity of the sympathetic nervous system is implicated in both benign and cancerous prostate disease, while the parasympathetic nervous system is also implicated in prostate cancer progression. The transport of sperm through the male reproductive tract is also controlled by the sympathetic nervous system making it important in male fertility and a possible target for nonhormonal male contraception.
Our research focuses on three interrelated receptor proteins that are the predominant mediators of smooth muscle contractility in male genitourinary tissues: the G protein-coupled α1A-adrenoceptor and M3 muscarinic receptors as well as the P2X1-purinoceptor ligand gated ion channel. Using pharmacological, biochemical, immunohistochemical and genetic approaches, we can study the role played by these receptors in male genitourinary function.
Inhibition of vas deferens contraction as a male contraceptive target
Vas deferens histochemistry and sperm viability in α1A-adrenoceptor and P2X1-purinoceptor double knockout mice.
The search for a viable male contraceptive target has been a medical challenge for many years. Most strategies have focused on hormonal or germline strategies to produce dysfunctional sperm that are incapable of fertilization. The problem with such approaches is that they have intolerable side effects such as affecting male sexual activity or causing long term irreversible effects on fertility. In addition, some strategies may transmit detrimental changes to future offspring. This project investigates a male contraceptive target within the autonomic nervous system, which would not affect the long term viability of sperm nor the sexual or general health of males. In addition, due to the nature of the target, the contraceptive has the potential to be orally administered. This project uses genetically modified mice to investigate the viability of this target using behavioural mating studies, isolated tissue experiments, sperm analysis, in vitro fertilization, immunohistochemistry and in vivo cardiovascular physiology experiments.
What makes the α1A-adrenoceptor gene elicit α1L-adrenoceptor pharmacology?
Colocalization of CXCR2 and α-actin within the stroma or the rat prostate gland.
The α1A-adrenoceptor is therapeutically exploited because of its prevalence in the lower urinary tract. The pharmacology shown by this lower urinary tract α1A-adrenoceptor is different from that shown by other α1A-adrenceptors, which has led to it being subclassified as an α1L-adrenoceptor. Only in the last few years, was it shown in our laboratory that this pharmacologically distinct α1L-adrenoceptor is a derivative of the α1A-adrenoceptor gene. This project investigates the possible molecular mechanisms by which the α1A-adrenoceptor gene is able to produce two pharmacologically distinct adrenoceptor subtypes. The project utilises cell lines transfected with α1A-adrenoceptors and native tissues which express α1A and α1L-adrenoceptors to investigate possible molecular mechanisms at play. The challenge remains to identify any interacting proteins and show the nature with which they change the pharmacology of the receptor for different ligands.
Control of smooth muscle contractility within the prostate gland
Likely intracellular signalling pathways controlling contractility of prostatic smooth muscle cells.
Benign prostatic hyperplasia (BPH) is the major cause of lower urinary tract symptoms in men aged 50 or older. Symptoms are not normally life threatening, but often drastically affect quality of life. Current drugs are only effective in treating mild to moderate symptoms, yet despite this no emerging contenders appear to be on the horizon. This is remarkable given the increasing number of patients with severe symptoms who are required to undergo invasive and unpleasant surgery. This project investigates novel drug targets focusing on drug targets which are able to relax prostatic smooth muscle in a similar way to the α1-adrenoceptor antagonists as this appears to be the most effective mechanism of action for the treatment of urinary symptoms associated with BPH. Recent basic research in our laboratory has revealed a number of novel drug targets such as muscarinic receptor or P2X-purinoceptor antagonists which have the potential to produce more effective and safer drug treatments.
GPCRs in prostate cancer
Cellular components of the prostate gland which make up the tumour microenvironment in prostate cancer (from Barron & Rowley, Endocrine-Related Cancer 2012; 19:R187–R204.
Our hypothesis is that G protein-coupled receptors (GPCRs), exemplified by the β2-adrenoceptor, the α1A-adrenoceptor and the M3 muscarinic acetylcholine receptor, activate signalling pathways that promote the progression and metastasis of prostate cancer. The significance of receptor-signalling systems is two-fold, (i) examining GPCR responses to endogenous hormones or neurotransmitters may provide us with novel insights into cancer progression or metastasis, and (ii) agonists or antagonists at key receptors may provide new avenues for cancer treatment, either as single agents or in combination with signalling pathway inhibitors. Our studies utilise an integrated approach incorporating cell based assays and in vivo mouse models that will provide multiple lines of evidence about which receptors and pathways are important in mediating the effects of endogenous agonists or therapeutic ligands on disease progression.
Dr Sab Ventura
JIAO Y., PRESTON S., GARCIA-BUSTOS J.F., BAELL J.B., VENTURA S, LE T., McNAMARA N., NGUYEN N., BOTTEON A., SKINNER C., DANNE J., ELLIS S., KOEHLER A.V., WANG T., CHANG B.C.H., HOFMANN A., JABBAR A. & GASSER R.B. Tetrahydroquinoxalines induce a lethal evisceration phenotype in Haemonchus contortus in vitro. International Journal for Parasitology: Drugs and Drug Resistance 2019; 9: 59-71.
DANTAS DA SILVA JUNIOR E., SATO M., MERLIN J., BROXTON N., HUTCHINSON D.S., VENTURA S., EVANS B.A. & SUMMERS R.J. Factors influencing biased agonism in recombinant cells expressing the human α1A-adrenoceptor. British Journal of Pharmacology 2017; 174: 2318-2333.
XIE J., MØLCK C., PAQUET-FIFIELD S., BUTLER L., AUSTRALIAN PROSTATE CANCER BIORESOURCE, SLOAN E., VENTURA S. & HOLLANDE F. High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. Oncotarget 2016; 7: 44492-44504.
CHAKRABARTY B., DEY A., LAM M., VENTURA S. & EXINTARIS B. Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea-pig prostate gland. Neurourology and Urodynamics 2015; 34: 482-488.
WHITE C.W., SHORT J.L., EVANS R.J. & VENTURA S. Development of a P2X1-purinoceptor mediated contractile response in the aged mouse prostate gland through slowing down of ATP breakdown. Neurourology and Urodynamics 2015; 34: 292-298.
WHITE C.W., CHOONG Y.-T., SHORT J.L., EXINTARIS B., MALONE D.T., ALLEN A.M., EVANS R.J. & VENTURA S. Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice. Proceedings of the National Academy of Sciences of the United States of America 2013; 110: 20825-20830.
OLIVER V.L., POULIOS K., VENTURA S. & HAYNES J.M. A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the epidermal growth factor receptor signalling cascade in prostate stromal cells. British Journal of Pharmacology 2013; 170: 592-601.
MUSTAFA S., SEE H.B., SEEBER R.M., ARMSTRONG S.P., WHITE C.W., VENTURA S., AKLI AYOUB M. & PFLEGER K.D.G. Identification and profiling of a novel α1A-adrenoceptor-CXC chemokine receptor 2 heteromer. Journal of Biological Chemistry 2012; 287: 12952-12965.
WHITE C.W., SHORT J.L., HAYNES J.M., MATSUI M. & VENTURA S. Contractions of the mouse prostate elicited by acetylcholine are mediated by M3 muscarinic receptors. Journal of Pharmacology and Experimental Therapeutics 2011; 339: 870-877.
WHITE C.W., SHORT J.L., HAYNES J.M., EVANS R.J. & VENTURA S. The residual nonadrenergic contractile response to nerve stimulation of the mouse prostate is mediated by acetylcholine but not ATP in a comparison with the mouse vas deferens. Journal of Pharmacology and Experimental Therapeutics 2010; 335: 489-496.
GRAY K.T., SHORT J.L. & VENTURA S. The α1A-adrenoceptor gene is required for the α1L-adrenoceptor-mediated response in isolated preparations of the mouse prostate. British Journal of Pharmacology 2008; 155: 103-109. recommended by Faculty 1000 Biology
WHITE C.W., DANTAS DA SILVA JUNIOR E., LIM L. & VENTURA S. What makes the α1A-adrenoceptor gene product assume a α1L-adrenoceptor phenotype? British Journal of Pharmacology 2019 https://doi.org/10.1111/bph.14599.
VENTURA S. Toward better treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia? American Journal of Physiology – Renal Physiology 2018; 315: F138-F139.
VENTURA S. & EVANS B.A. Does the autonomic nervous system contribute to the initiation and progression of prostate cancer? Asian Journal of Andrology 2013; 15(6):715-716.
WHITE C.W., XIE J.H. & VENTURA S. Age related changes in the innervation of the prostate gland: implications for prostate cancer initiation and progression. Organogenesis 2013; 9: 159-168.
VENTURA S. What makes the α1A-adrenoceptor gene express the α1L-adrenoceptor functional phenotype? British Journal of Pharmacology 2012; 165: 1223-1225.
VENTURA S., OLIVER V.L., WHITE C.W., XIE J.H., HAYNES J.M. & EXINTARIS B. Novel drug targets for the pharmacotherapy of benign prostatic hyperplasia (BPH). British Journal of Pharmacology 2011; 163: 891-907.
VENTURA S., PENNEFATHER J.N. & MITCHELSON F.J. Cholinergic innervation and function in the prostate gland. Pharmacology and Therapeutics 2002; 94: 93-112.
Dr Betty Exintaris
Yaakob N, Nguyen DT, Exintaris B, Irving HR. (2018) The C and E subunits of the serotonin 5-HT3 receptor subtly modulate electrical properties of the receptor. Biomedicine & Pharmacotherapy 97:1701-1709.
Kügler R, Mietens A, Seidensticker M, Tasch S, Wagenlehner FM, Kaschtanow A, Tjahjono Y, Tomczyk CU, Beyer D, Risbridger GP, Exintaris B, Ellem SJ, Middendorff R (2017) Novel imaging of the prostate reveals spontaneous gland contraction and excretory duct quiescence together with different drug effects. FASEB J. 32(3):1130-1138.
Lee SN, Chakrabarty B, Wittmer B, Papargiris M, Ryan A, Frydenberg M, Lawrentschuk N, Middendorff R, Risbridger GP, Ellem SJ, Exintaris B (2017) Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate. Sci Rep. 7(1):10150.
White PJ, Larson I, Styles K, Yuriev E, Evans DR, Rangachari PK, Short JL, Exintaris B, Malone DT, Davie B, Eise N, McNamara K, Naidu S. (2016) Adopting an active learning approach to teaching in a research-intensive higher education context transformed staff teaching attitudes and behaviours. Higher Education Research & Development 35(3), 619-633.
Chakrabarty B, Dey A, Lam M, Ventura S, Exintaris B (2014) Tamsulosin modulates, but does not abolish the spontaneous activity in the guinea pig prostate gland. Neurourol Urodyn. 34(5):482-488.
White CW, Choong YT, Short JL, Exintaris B, Malone DT, Allen AM, Evans RJ, Ventura S. (2013) Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice. Proc Natl Acad Sci U S A. 110(51):20825-20830.
Lam M, Dey A, Lang RJ, Exintaris B (2013) Effects of imatinib mesylate on the spontaneous activity generated by the guinea-pig prostate. BJU Intl. 112(4):E398-405.
Lam M, Kerr KP, Exintaris B. (2013) Involvement of Rho-kinase signaling pathways in nerve evoked and spontaneous contractions of the Guinea pig prostate. J Urol. 189(3):1147-54.
Dey A, Lang RJ & Exintaris B. (2012) Nitric oxide signalling pathways involved in the inhibition of spontaneous activity in the Guinea pig prostate. J Urol. 187(6):2254-2260.
Lam M, Shigemasa Y, Exintaris B, Lang RJ, Hashitani H.(2011) Spontaneous Ca2+ signaling of interstitial cells in the guinea pig prostate. J Urol. 186(6):2478-2486.
Yaakob N, Malone DT, Exintaris B, Irving HR. (2011) Heterogeneity amongst 5-HT₃ receptor subunits: is this significant? Curr Mol Med. 11(1):57-68.
Lam M, Kerr K, Ventura S, Exintaris B. (2011) Extracellular Ca(2+) entry and mobilization of inositol trisphosphate-dependent Ca(2+) stores modulate histamine and electrical field stimulation induced contractions of the guinea-pig prostate. Pharmacol Res. 64(3):235-241.
Nguyen DT, Dey A, Lang RJ, Ventura S, Exintaris B. (2011) Contractility and pacemaker cells in the prostate gland. J Urol. 2011 185(1):347-51.
Dey A, Kusljic S, Lang RJ, Exintaris B. (2010) Role of connexin 43 in the maintenance of spontaneous activity in the guinea pig prostate gland. Br J Pharmacol. 2010 161(8):1692-1707.
Kusljic S, Exintaris B. (2010) The effect of estrogen supplementation on cell proliferation and expression of c-kit positive cells in the rat prostate. Prostate. 2010 70(14):1555-1562.
Tokanovic S, White CW, Malone DT, Exintaris B, Ventura S. (2010) Characterisation of the prostanoid receptor mediating inhibition of smooth muscle contractility in the rat prostate gland. Naunyn Schmiedebergs Arch Pharmacol. 381(4):321-328.
Dey A, Nguyen D-T, Lang RJ & Exintaris B. (2009) Spontaneous Electrical Waveforms in Aging Guinea-pig Prostates. J Urol. 181(6):2797-2805
Exintaris B, Nguyen D-T, Lam M, Lang RJ. (2009) IP3 dependent Ca2+ stores and mitochondria modulate slow wave activity arising from the smooth muscle cells of the guinea-pig prostate gland. Br J Pharmacol 156(7):1098-1106.
Nguyen, D-T, Lang RJ, Exintaris, B. (2009) α1-adrenoceptor modulation of spontaneous electrical waveforms in the guinea-pig prostate. Eur J Pharmacol. 608(1-3):62-70.
Patak E, Pennefather JN, Gozali M, Candenas L, Kerr K, Exintaris B, Ziccone S, Potteck H, Chetty N, Page NM, Pinto F. (2008) Functional characterisation of hemokinin-1 in the mouse uterus. Eur J Pharmacol 601(1-3):148-153.
Kusljic S, Dey A, Nguyen D-T, Lang RJ, Exintaris B. (2008) Prostatic interstitial cells in ageing guinea-pig prostates. Current Urology 1: 141-144.
Ventura, S, Oliver V, White C, Xie A, Haynes J, Exintaris B. (2011) Novel drug targets for the pharmacotherapy of benign prostatic hyperplasia (BPH) Br J Pharmacol. 163(5):891-907.
Chakrabarty B, Lee S, Exintaris B (2019) Generation and Regulation of Spontaneous Contractions in the Prostate. In: Hashitani H, Lang RJ. (Editors). Smooth Muscle Spontaneous Activity: Physiological and Pathological Modulation. Singapore: Springer Publishing Company.
What makes the α1A-adrenoceptor gene elicit α1L-adrenoceptor pharmacology?
- Dr Dana Hutchinson, Drug Discovery Biology, MIPS
- Professor Roger J Summers, Drug Discovery Biology, MIPS
- Dr Bronwyn A Evans, Drug Discovery Biology, MIPS
- Dr Lauren T May, Drug Discovery Biology, MIPS
- Dr Carl White, School of Life Sciences, University of Nottingham
Control of smooth muscle contractility in the prostate gland
- Dr John M Haynes, Drug Discovery Biology, MIPS
Ms Nicole Eise
Ms Eunice Su