Paul Micevych, Ph.D.

Work Address:
Los Angeles, CA 90095 CHS
Los Angeles, CA 90095

Distinguished Professor, Head and Neck Surgery
Chair and Distinguished Professor, Neurobiology
Member, Brain Research Institute, Molecular, Cellular & Integrative Physiology GPB Home Area, Neuroscience GPB Home Area
Research Interests
The research of the laboratory is focused on steroid hormone interactions with the central nervous system. Throughout life, sex steroid hormones profoundly influence the structure and function of specific circuits that regulate reproduction and reproductive behaviors. Previous work had focused on the regulation of neuropeptide and transmitter expression. However, relatively little is known about the mechanisms by which steroids affect postsynaptic activation and signal transduction. The laboratory has three major interests: STEROID MODULATION OF mu-OPIOID RECEPTOR (MOR) ACTIVATION Estrogen treatment of ovariectomized rats initially has an inhibitory action on circuits mediating sexual receptivity (lordosis), but eventually induces sexual receptivity. We have determined that an important component of this inhibition is due to the activation of MOR circuits in the medial preoptic area. Taking advantage of G protein-coupled receptor (GPCR) internalization following activation of the receptor by an endogenous ligand, we determined that activation of MOR is correlated with an inhibition of lordosis. Behaviorally, progesterone augments estrogen action. We have determined that progesterone relieves MOR-mediated inhibition, through the termination of opioid release in the medial preoptic area. Is the MOR-inhibition dependent on estrogen receptors? Working with Dr. Emilie Rissman, (University of Virginia), we have determined that estrogen activation of MOR circuits is dependent on the expression of the estrogen receptor-a (ERa). Although MOR and opioid expression appears nominal in ERa knockout (ERaKO) mice, and MOR-selective opioids internalize MOR, estrogen does not induce internalization. These results and the rapid time course of internalization suggest that the ERa is acting through a nongenomic mechanism. REGULATION OF NEUROSTEROID BIOSYNTHESIS Although it is well known that the brain can synthesize neurosteroids, it has been difficult to determine the function of these steroids in the regulation of reproduction. We have recently determined that peripheral estrogen stimulates the synthesis of progesterone in the hypothalamus. This increased in progesterone is restricted to the hypothalamus and is necessary for the initiation of the LH surge. Examination of cells in vitro suggest that astrocytes are responsible for the estrogen-induced progesterone synthesis. This response to estrogen may be an important component of estrogen positive feedback regulates the LH surge. Males and aging females that do not exhibit positive feedback, that are lacking the ability to increase progesterone synthesis in the hypothalamus. NONGENOMIC ACTIONS OF ESTROGEN MODULATION To begin examining the nongenomic actions of estrogen on regulation of postsynaptic mechanisms, we have studied the response of Ca2+ in dorsal root ganglion (DRG) cells. DRG cells provide an accessible and practical solution to quantitatively study the chemosensitive properties of estrogen-sensitive neurons. These cells express ERa and a number of other well characterized Ca2+ channels. We have been studying the effects of estrogen on modulation of P2X receptors (ATP receptors) and activity of voltage dependent Ca2+ channels (VdCC) using digital videomicroscopy for [Ca2+]i changes. Recent results indicate that 17-beta estradiol inhibited ATP-mediated [Ca2+]i responses and attenuated Ca2+ rise by acting on L-type VDCC in both male and female DRG neurons

Research efforts in the Micevych laboratory involve understanding the cellular and molecular events underlying estrogen action on neurons and glial cells. Estrogen has profound effects on cognitive function and neuroprotection, as well as, reproductive functions. Estrogen affects the expression and activity of various neuropeptides and sex steroids. In particular they have focused on regulation mu-opioid and nociceptin receptors in the CNS regulation of sexual behavior. Recent experiments have demonstrated the synthesis of progesterone in the brain, its regulation by estrogen and physiologic functions of neuroprogesterone. RT-PCR and calcium imaging experiments in neurons and astrocytes have been used to elucidate the mechanisms of estrogen rapid signaling in both glial cells and neurons. The Micevych laboratory has demonstrated that estrogen can modulate nociceptive signaling through rapid actions on primary sensory neurons demonstrating a novel mechanism of estrogen modulation of pain. Additionally, the Micevych Laboratory has been studying the neuroprotective action of estrogen in the nigrostriatal dopamine system. Estrogen activates the insulin-like growth factor-1 (IGF-1) to ameliorate a hallmark of ParkinsonA?s disease A? the neurodegeneration of dopamine neurons. Significantly, estrogen or IGF-1 is efficacious after either central or peripheral administration. Together these experiments underscore the broad range of estrogen signaling influencing both physiology and pathology.


A selected list of publications:

Christensen Amy, Micevych Paul   A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a Neuroendocrinology, 2013; 97(4): 363-8.
Dominguez Reymundo, Dewing Phoebe, Kuo John, Micevych Paul   Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons Steroids, 2013; 78(6): 607-13.
Sinchak Kevin, Dewing Phoebe, Ponce Laura, Gomez Liliana, Christensen Amy, Berger Max, Micevych Paul   Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors Hormones and behavior, 2013; 64(1): 136-43.
Christensen Amy, Micevych Paul   CAV1 siRNA reduces membrane estrogen receptor-α levels and attenuates sexual receptivity Endocrinology, 2012; 153(8): 3872-7.
Micevych Paul E, Kelly Martin J   Membrane estrogen receptor regulation of hypothalamic function Neuroendocrinology, 2012; 96(2): 103-10.
Micevych Paul, Christensen Amy   Membrane-initiated estradiol actions mediate structural plasticity and reproduction Frontiers in neuroendocrinology, 2012; 33(4): 331-41.
Micevych Paul   Membrane-initiated estradiol signaling regulates the central nervous system Frontiers in neuroendocrinology, 2012; 33(4): 329-30.
Kuo John, Micevych Paul   Neurosteroids, trigger of the LH surge The Journal of steroid biochemistry and molecular biology, 2012; 131(1-2): 57-65.
Chaban Victor, Li Jichang, McDonald John S, Rapkin Andrea, Micevych Paul   Estradiol attenuates the adenosine triphosphate-induced increase of intracellular calcium through group II metabotropic glutamate receptors in rat dorsal root ganglion neurons Journal of neuroscience research, 2011; 89(11): 1707-10.
Christensen Amy, Dewing Phoebe, Micevych Paul   Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(48): 17583-9.
Micevych Paul E, Dewing Phoebe   Membrane-initiated estradiol signaling regulating sexual receptivity Frontiers in endocrinology, 2011; 2(11): 26.
Micevych Paul, Sinchak Kevin   The Neurosteroid Progesterone Underlies Estrogen Positive Feedback of the LH Surge Frontiers in endocrinology, 2011; 2(11): 90.
Dominguez Reymundo, Micevych Paul   Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010; 30(38): 12589-96.
Micevych Paul, Bondar Galyna, Kuo John   Estrogen actions on neuroendocrine glia Neuroendocrinology, 2010; 91(3): 211-22.
Kuo John, Hamid Naheed, Bondar Galyna, Prossnitz Eric R, Micevych Paul   Membrane estrogen receptors stimulate intracellular calcium release and progesterone synthesis in hypothalamic astrocytes The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010; 30(39): 12950-7.
Kuo John, Hamid Naheed, Bondar Galyna, Dewing Phoebe, Clarkson Jenny, Micevych Paul   Sex differences in hypothalamic astrocyte response to estradiol stimulation Biology of sex differences, 2010; 1(1): 7.
Quesada Arnulfo, Micevych Paul, Handforth Adrian   C-terminal mechano growth factor protects dopamine neurons: a novel peptide that induces heme oxygenase-1 Experimental neurology, 2009; 220(2): 255-66.
Bondar Galyna, Kuo John, Hamid Naheed, Micevych Paul   Estradiol-induced estrogen receptor-alpha trafficking The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009; 29(48): 15323-30.
Micevych Paul, Dominguez Reymundo   Membrane estradiol signaling in the brain Frontiers in neuroendocrinology, 2009; 30(3): 315-27.
Kuo John, Hariri Omid R, Bondar Galyna, Ogi Julie, Micevych Paul   Membrane estrogen receptor-alpha interacts with metabotropic glutamate receptor type 1a to mobilize intracellular calcium in hypothalamic astrocytes Endocrinology, 2009; 150(3): 1369-76.
Micevych Paul, Sinchak Kevin   Estradiol regulation of progesterone synthesis in the brain Molecular and cellular endocrinology, 2008; 290(1-2): 44-50.
Quesada Arnulfo, Micevych Paul   Estrogen and progesterone modulate [35S]GTPgammaS binding to nociceptin receptors Neuroendocrinology, 2008; 88(1): 35-42.
Li Jichang, Micevych Paul, McDonald John, Rapkin Andrea, Chaban Victor   Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats Journal of neuroscience research, 2008; 86(12): 2746-52.
Micevych Paul E, Mermelstein Paul G   Membrane estrogen receptors acting through metabotropic glutamate receptors: an emerging mechanism of estrogen action in brain Molecular neurobiology, 2008; 38(1): 66-77.
Mermelstein Paul G, Micevych Paul E   Nervous system physiology regulated by membrane estrogen receptors Reviews in the neurosciences, 2008; 19(6): 413-24.
Micevych Paul, Soma Kiran K, Sinchak Kevin   Neuroprogesterone: key to estrogen positive feedback? Brain research reviews, 2008; 57(2): 470-80.
Quesada Arnulfo, Lee Becky Y, Micevych Paul E   PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease Developmental neurobiology, 2008; 68(5): 632-44.
Dewing P, Christensen A, Bondar G, Micevych P.   PKC signaling in the hypothalamic arcuate nucleus regulates sexual receptivity in female rats, Endocrinology, 2008; .
Dewing Phoebe, Christensen Amy, Bondar Galyna, Micevych Paul   Protein kinase C signaling in the hypothalamic arcuate nucleus regulates sexual receptivity in female rats Endocrinology, 2008; 149(12): 5934-42.
Micevych Paul, Sinchak Kevin   Synthesis and function of hypothalamic neuroprogesterone in reproduction Endocrinology, 2008; 149(6): 2739-42.
Quesada Arnulfo, Romeo Horacio E, Micevych Paul   Distribution and localization patterns of estrogen receptor-beta and insulin-like growth factor-1 receptors in neurons and glial cells of the female rat substantia nigra: localization of ERbeta and IGF-1R in substantia nigra The Journal of comparative neurology, 2007; 503(1): 198-208.
Micevych Paul E, Chaban Victor, Ogi Julie, Dewing Phoebe, Lu John K H, Sinchak Kevin   Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures Endocrinology, 2007; 148(2): 782-9.
Dewing Phoebe, Boulware Marissa I, Sinchak Kevin, Christensen Amy, Mermelstein Paul G, Micevych Paul   Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007; 27(35): 9294-300.
Poulsen DJ, Standing D, Bullshields K, Spencer K, Micevych PE, Babcock AM.   Overexpression of hippocampal Ca2+/calmodulin-dependent protein kinase II improves spatial memory, J Neurosci Res, 2007; 85(4): 735-9.
Sinchak Kevin, Dewing Phoebe, Cook Misty, Micevych Paul   Release of orphanin FQ/nociceptin in the medial preoptic nucleus and ventromedial nucleus of the hypothalamus facilitates lordosis Hormones and behavior, 2007; 51(3): 406-12.
Chaban Victor, Christensen Amy, Wakamatsu Micah, McDonald Michelle, Rapkin Andrea, McDonald John, Micevych Paul   The same dorsal root ganglion neurons innervate uterus and colon in the rat Neuroreport, 2007; 18(3): 209-12.
Dewing Phoebe, Chiang Charleston W K, Sinchak Kevin, Sim Helena, Fernagut Pierre-Olivier, Kelly Sabine, Chesselet Marie-Francoise, Micevych Paul E, Albrecht Kenneth H, Harley Vincent R, Vilain Eric   Direct regulation of adult brain function by the male-specific factor SRY Current biology : CB, 2006; 16(4): 415-20.
Micevych PE, Chaban V, Ogi J, Dewing P, Lu JK, Sinchak K.   Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures, Endocrinology, 2006; 148(2): 782-9.
Quesada Arnulfo, Micevych Paul   Estrogen and CCK1 receptor modification of mu-opioid receptor binding in the cortex of female rats Brain research, 2006; 1073-1074(4): 316-20.
Sinchak Kevin, Romeo Horacio E, Micevych Paul E   Site-specific estrogen and progestin regulation of orphanin FQ/nociceptin and nociceptin opioid receptor mRNA expression in the female rat limbic hypothalamic system The Journal of comparative neurology, 2006; 496(2): 252-68.
Chaban Victor V, Micevych Paul E   Estrogen receptor-alpha mediates estradiol attenuation of ATP-induced Ca2+ signaling in mouse dorsal root ganglion neurons Journal of neuroscience research, 2005; 81(1): 31-7.
Soma KK, Sinchak K, Lakhter A, Schlinger BA, Micevych PE.   Neurosteroids and female reproduction: estrogen increases 3beta-HSD mRNA and activity in rat hypothalamus, Endocrinology, 2005; 146(10): 4386-90.
Sinchak Kevin, Shahedi Kamyar, Dewing Phoebe, Micevych Paul   Sexual receptivity is reduced in the female mu-opioid receptor knockout mouse Neuroreport, 2005; 16(15): 1697-700.
Chaban Victor V, Lakhter Alexander J, Micevych Paul   A membrane estrogen receptor mediates intracellular calcium release in astrocytes Endocrinology, 2004; 145(8): 3788-95.
Sinchak Kevin, Mills Richard H, Tao Leslie, LaPolt Philip, Lu John K H, Micevych Paul   Estrogen induces de novo progesterone synthesis in astrocytes Developmental neuroscience, 2003; 25(5): 343-8.
Quesada Arnulfo, Micevych Paul E   Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions Journal of neuroscience research, 2004; 75(1): 107-16.
Mills Richard H, Sohn Richard K, Micevych Paul E   Estrogen-induced mu-opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y-Y1 receptor activation in the arcuate nucleus of female rats The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004; 24(4): 947-55.
Sinchak Kevin, Mills Richard H, Eckersell Clair B, Micevych Paul E   Medial preoptic area delta-opioid receptors inhibit lordosis Behavioural brain research, 2004; 155(2): 301-6.
Saldanha Colin J, Schlinger Barney A, Micevych Paul E, Horvath Tamas L   Presynaptic N-methyl-D-aspartate receptor expression is increased by estrogen in an aromatase-rich area of the songbird hippocampus The Journal of comparative neurology, 2004; 469(4): 522-34.
Chaban VV, Mayer EA, Ennes HS, Micevych PE.   Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons, Neuroscience, 2003; 118(4): 941-8.
Sinchak Kevin, Mills Richard H, Tao Leslie, LaPolt Philip, Lu John K H, Micevych Paul   Estrogen induces de novo progesterone synthesis in astrocytes Developmental neuroscience, 2003; 25(5): 343-8.
Micevych Paul E, Rissman Emilie F, Gustafsson Jan-Ake, Sinchak Kevin   Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor internalization Journal of neuroscience research, 2003; 71(6): 802-10.
Micevych Paul, Sinchak Kevin, Mills Richard H, Tao Leslie, LaPolt Philip, Lu John K H   The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats Neuroendocrinology, 2003; 78(1): 29-35.
Sinchak Kevin, Micevych Paul   Visualizing activation of opioid circuits by internalization of G protein-coupled receptors Molecular neurobiology, 2003; 27(2): 197-222.
Cristobal Ricardo, Popper Paul, Lopez Ivan, Micevych Paul, De Vellis Jean, Honrubia Vicente   In vivo and in vitro localization of brain-derived neurotrophic factor, fibroblast growth factor-2 and their receptors in the bullfrog vestibular end organs Brain research. Molecular brain research, 2002; 102(1-2): 83-99.
Micevych Paul, Chaban Victor, Quesada Arnulfo, Sinchak Kevin   Oestrogen modulates cholecystokinin: opioid interactions in the nervous system Pharmacology & toxicology, 2002; 91(6): 387-97.
Mills Richard H, Romeo Horacio E, Lu John K H, Micevych Paul E   Site-specific decrease of progesterone receptor mRNA expression in the hypothalamus of middle-aged persistently estrus rats Brain research, 2002; 955(1-2): 200-6.
Raji-Kubba Juman, Micevych Paul E, Simmons Dwayne D   The superior olivary complex of the hamster has multiple periods of cholinergic neuron development Journal of chemical neuroanatomy, 2002; 24(2): 75-93.
Micevych, P Sinchak, K   Estrogen and endogenous opioids regulate CCK in reproductive circuits Peptides. , 2001; 22(8): 1235-44.
Tiwari-Woodruff SK, Buznikov AG, Vu TQ, Micevych PE, Chen K, Kornblum HI, Bronstein JM   OSP/claudin-11 forms a complex with a novel member of the tetraspanin super family and beta1 integrin and regulates proliferation and migration of oligodendrocytes, J Cell Biol, 2001; 153(2): 295-305.
Sinchak, K Micevych, PE   Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior The Journal of neuroscience : the official journal of the Society for Neuroscience. , 2001; 21(15): 5723-9.
Sinchak, K Eckersell, C Quezada, V Norell, A Micevych, P   Preproenkephalin mRNA levels are regulated by acute stress and estrogen stimulation Physiology & behavior. , 2000; 69(4-5): 425-32.
Nansen, EA Jokel, ES Lobo, MK Micevych, PE Ariano, MA Levine, MS   Striatal ionotropic glutamate receptor ontogeny in the rat Developmental neuroscience. , 2000; 22(4): 329-40.
Lewis, MI Fournier, M Yeh, AY Micevych, PE Sieck, GC   Alterations in diaphragm contractility after nandrolone administration: an analysis of potential mechanisms Journal of applied physiology (Bethesda, Md. : 1985) , 1999; 86(3): 985-92.
Popper, P Lopez, I Beizai, P Li, G Kim, J Micevych, PE Honrubia, V   Expression of BDNF and TrkB mRNAs in the crista neurosensory epithelium and vestibular ganglia following ototoxic damage Brain research. , 1999; 846(1): 40-51.
Lopez, I., Honrubia,V., Lee, S.-C., Chung, W.-H., Li, G., Beykirch, K., and Micevych, P.   The protective effect of Brain-derived neurotrophic factor after gentomicin ototoxicity, Am. J. Otology , 1999; 20: 317-324.
Eckersell, CB Popper, P Micevych, PE   Estrogen-induced alteration of mu-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala The Journal of neuroscience : the official journal of the Society for Neuroscience. , 1998; 18(10): 3967-76.
Holland, K., Abelson, L. P and Micevych, P.E   Ontogeny and estrogen regulation of prepubertal CCK and preproenkephalin mRNA in the hypothalamus and limbic system, J. Comp. Neurol, 1998; 392: 48 - 57.
Don, DM Newman, AN Micevych, PE Popper, P   Expression of brain-derived neurotrophic factor and its receptor mRNA in the vestibuloauditory system of the bullfrog Hearing research. , 1997; 114(1-2): 10-20.
Holland, K. Popper, P. and Micevych, P.E   Infusions of CCKA receptor mRNA antisense oligodeoxynucleotides inhibit lordosis behavior, Physiol. and Behav, 1997; 62: (537- 543).
Eckersell C. and Micevych, P.E   Opiate receptors modulate estrogen-induced cholecystokinin and trachykinin but not enkephalin mRNA levels in the limbic system and hypothalamus, Neuroscience, 1997; 80: (473-485).
Sinchak, K., D. Hendricks, R. Baroudi, and P. E Micevych   Orphanin FQ/Nociceptin in the ventromedial nucleus facilitates lordosis, NeuroReport, 1997; 8: 3857 - 3860.
Blanco, C., Popper, P. and Micevych, P. E   Pharmacological doses of testosterone and up-regulate choline-acetyltransferase mRNA, Neuroscience, 1997; 78(3): 873 - 882.
Olive, MF Anton, B Micevych, P Evans, CJ Maidment, NT   Presynaptic versus postsynaptic localization of mu and delta opioid receptors in dorsal and ventral striatopallidal pathways The Journal of neuroscience : the official journal of the Society for Neuroscience. , 1997; 17(19): 7471-9.