Ph.D., Cornell University, 1981

Pharmacology and medicinal chemistry of sigma receptors and opioid receptors

Sigma receptors as therapeutic and diagnostic targets.

Sigma receptors and drug-induced apoptosis.

Signal transduction mechanisms in receptor-mediated apoptosis and regulation of cell proliferation.

Small molecule drug design.


My general interests have centered on biochemical mechanisms involved in the action of opiate drugs, opioid peptides, and related compounds. Current research in this laboratory is directed at elucidation of the structure and function of sigma receptors. Sigma receptors (formerly classified as opioid receptors) are membrane-bound proteins that recognize several important classes of psychotropic drugs, including antipsychotic agents such as haloperidol, the psychotomimetic agent phencyclidine (PCP), some synthetic opiates such as pentazocine, and some psychostimulants like cocaine. Sigma-1 and sigma-2 receptor subtypes are currently known, and likely comprise a novel receptor family distinct from any known neurotransmitter or hormone receptor system. Both subtypes are present in the CNS as well as in peripheral tissues, and are expressed in high density in a number of neuronal and non-neuronal tumor cell lines. No endogenous ligands for these receptors have yet been clearly identified, although there is existing evidence for such substances and progesterone and other neurosteroids have been shown to interact with sigma-1 receptors.

Most work in our laboratory currently focuses on the possible role of sigma-2 receptors in regulation of cell proliferation and survival. We have found that chronic activation of sigma-2 receptors induces apoptosis in a wide variety of cell types. We are investigating the signaling mechanisms leading to the induction of cell death, and have found that these mechanisms are cell type-specific. For example, in breast tumor cells, apoptosis occurs via a novel mechanism that is both caspase- and p53-independent, whereas in a neuroblastoma line, cell death is dependent on caspase 8/10 activation. Signaling involves both transient and sustained changes in cytosolic calcium levels. We are interested in determining the mechanisms of calcium flux and the downstream effects of these calcium signals. Signaling also involves changes in cellular sphingolipids (ceramides and lysosphingolipids). Sphingolipids are involved in myriad cellular processes including cell survival, regulation of ion channels, and cell-cell recognition. Lysosphingolipids act via specific G-protein coupled receptors on the cell surface, as well as through certain intracellular targets, and ceramides are known to modulate the activity of various protein kinases and phosphatases involved in cell growth. We are investigating the role of sphingolipid signaling in neuronal and non-neuronal cells and how this system interfaces with sigma-2 receptors. Also under investigation are effects of sigma-2 receptor activation on mitochondria. Apoptosis in both neuronal and non-neuronal cell types appears to be dependent on loss of mitochondrial membrane potential and release of mitochondrial apoptogenic factors. The roles of mitochondrial pro- and anti-apoptotic Bcl-2 family proteins are under study. Finally, the sigma-2 receptor, a 21.5 kDa lipid raft protein, has not yet been cloned. We have projects underway aimed at purifying sigma-2 receptor proteins, obtaining protein sequence information, and using this information to clone the sigma-2 receptor gene.

The sigma-1 receptor has been cloned and is a 25 kDa polypeptide with two putative transmembrane domains. In contrast to sigma-2 receptors, activation of sigma-1 receptors appears to exert protective and perhaps trophic effects on neurons and other cell types. Others have shown that activation of sigma-1 receptors potentiates neurite outgrowth in culture, whereas we have shown that activation of sigma-2 receptors causes neurite retraction. Blockade of sigma-1 receptors by selective antagonists or antisense deoxyoligonucleotides has been shown to block the toxic effects of cocaine, a psychotropic agent that binds to sigma-1 receptors. Furthermore, sigma-1 receptor activation in the hippocampus has a cognitive enhancing effect. We have initiated structure-function studies of the sigma-1 receptor and its role in tumor cell proliferation and survival. Sigma-1 receptors regulate calcium signaling by amplifying release of calcium from the endoplasmic reticulum in response to the rise in IP3 via GPCR activation. The sigma-1 receptor appears to signal solely by protein-protein interactions. The liganded receptor binds to ankyrin in the ER membrane and relieves a tonic inhibition of the IP3 receptor that is imparted by its interaction with ankyrin. We have shown that stable overexpression of sigma-1 receptors induces a constitutive activation of the IP3 receptor in human MCF-7 breast tumor cells, which are normally devoid of sigma-1 receptors. Furthermore, studies using various receptor constructs showed that only the C-terminal segment of the receptor is required for this effect. We are further delineating the functional domains of the receptor. Furthermore, cells overexpressing active sigma-1 constructs proliferate more rapidly than untransfected cells and have a survival advantage. We are investigating the signaling mechanisms that are involved in inducing what appears to be a more highly aggressive phenotype. The studies suggest that the sigma-1 receptor could be a biomarker for assessing proliferative status of tumor cells.

We are involved in the design and synthesis of novel small molecule ligands for sigma-1 and sigma-2 receptors. Since the natural ligand(s) is unknown and many existing sigma ligands interact with other receptors, selective synthetic probes for sigma receptors are necessary. Through close collaboration with medicinal chemists, we have developed and are continuing to develop highly selective receptor agonists and antagonists for use as tools to study receptor function. We are interested in elucidating the structural features of ligands that determine binding affinity, impart subtype selectivity, and that specify agonist/antagonist properties. Some of these compounds may have clinical potential as therapeutic agents.

Studies of sigma receptors will shed light on novel modes for regulation of cell proliferation and survival. It may be possible to target sigma-2 receptors with agonists or sigma-1 receptors with antagonists to induce apoptosis in tumors rendered drug-resistant due to acquisition of mutations in key components of the classical apoptotic pathway, such as p53 and caspases. Sigma receptors in the CNS could conceivably play a role in neurodegenerative disorders. Furthermore, since typical neuroleptics such as haloperidol activate sigma-2 receptors, these studies may have important implications for treatment of psychiatric disorders with respect to the debilitating motor side effects induced by these agents.

Wayne Bowen has been teaching since 1983. He began with teaching introductory biology and endocrinology at Brown University. He later provided neuroscience lectures to undergraduate students, which he is still doing today. He has also taught biochemistry seminar courses to graduate students. While at NIH, he chaired the Department of Pharmacology and Toxicology of the NIH-Foundation for Advanced Education in the Sciences (FAES) Graduate School (1999 - 2004). He is currently co-directing the pharmacology component of the Integrated Pathophysiology/Pharmacology course in the Brown University Medical School. Over the course of his career, he has advised over 40 undergraduates in research projects in his laboratory. He has served as a Human Biology concentration advisor in the Health and Disease and Brain and Behavior tracks. He has directed the research of 4 graduate students and 11 postdoctoral fellows.

Directed Research/Independent Studies (BIOL 1950)
Directed Research/Independent Studies (BIOL 1960)
Endocrinology (BIOL 0030)
Graduate Independent Study (BIOL 2980)
Independent Study (NEUR 1970)
Integrated Medical Sciences III – System-Based Pharmacology; course Co-Director (BIOL 3667)
Integrated Medical Sciences IV – System-Based Pharmacology; course Co-Director (BIOL 3676)
Receptor, Channels and Signaling (BIOL 2170)
The Brain: An Introduction to Neuroscience (NEUR 0010)

• Wei, Z., Qi, J., Dai, Y., Bowen, W.D., and Mousseau, D.D. (2009) Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function. Cellular Signalling 21: 161-168.
• Wu, Z. and Bowen, W.D. (2008) Role of sigma-1 receptor C-terminal segment in inositol 1,4,5-trisphosphate receptor activation: Constitutive enhancement of calcium signaling in MCF-7 tumor cells. J. Biol. Chem. 283: 28198-28215.
• Martin-Fardon, R., Maurice, T., Aujla, H., Bowen, W.D., and Weiss, F. (2007) Diffferential effects of sigma-1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs. natural reward. Neuropsychopharmacol. 32: 1967-1973.
• Gebreselassie, D. and Bowen, W.D. (2004) Sigma-2 receptors are specifically localized to lipid rafts of rat liver membranes. Eur. J. Pharmacol. 493: 19-28.
• Matsumoto, R.R., Potelleret, F.H., Mack, A., Pouw, B., Zhang, Y., and Bowen, W.D. (2004) Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies. Pharmacol. Biochem. Behav. 77: 775-781.
• Romieu, P., Martin-Fardon, R., Bowen, W.D., and Maurice, T. (2003) Sigma1 receptor-related neuroactive steroids modulate cocaine-induced reward. J. Neurosci. 23: 3572-3576.
• Cao, J.J., Kulkarni, S.S., Husbands, S.M., Bowen, W.D., Williams, W., Kopajtic, T., Katz, J.L., George, C., and Newman, A.H. (2003) Dual probes for the dopamine transporter and the sigma-1 receptors: Novel piperazinyl alkyl-bis-(4'-fluorophenyl)amine analogs as potential cocaine-abuse therapeutics. J. Med. Chem. 46: 2589-2598.
• Crawford, K.W., Bittman, R., Chun, J., Byun, H.S., and Bowen, W.D. (2003) Novel ceramide analogs display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells. Cell. Mol. Biol. 49: 1017-1023.
• Crawford, K.W. and Bowen, W.D. (2002) Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res. 62: 313-322.
• Crawford, K.W., Coop, A., and Bowen, W.D. (2002) Sigma-2 receptors regulate changes in sphingolipid levels in breast tumor cells. Eur. J. Pharmacol. 443: 207-209.
• Matsumoto, R.R., McCracken, K.A., Pouw, B., Zhang, Y., and Bowen, W.D. (2002) Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. Neuropharmacol. 42: 1043-1055.
• Vilner, B.J. and Bowen, W.D. (2000) Modulation of cellular calcium by sigma-2 receptors: Release from intracellular stores in human SK-N-SH neuroblastoma cells. J. Pharmacol. Exp. Ther. 292: 900-911.
• John, C.S., Vilner, B.J., Geyer, B.C., Moody, T., and Bowen, W.D. (1999) Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors. Cancer Res. 59: 4578-4583.