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Melvin Billingsley
Title Professor
Institution College of Medicine
Department Pharmacology
Address 500 University Drive Hershey PA 17033
Mailbox: R131
Telephone 7176352100
Email
Background
PREFERRED TITLE/ROLE:

President and CEO of Life Sciences Greenhouse, Professor of Pharmacology

GRADUATE PROGRAM AFFILIATIONS:

Integrative Biosciences, MD/PhD Degree Program, Pharmacology, Neuroscinces

EDUCATION:

Ph.D., George Washington University, 1981
Postdoctoral Training, Yale University School of Medicine, 1981-1982
Staff Fellow, National Heart, Lung and Blood Institute

NARRATIVE:

There are three major research interests in this laboratory. One area of active investigation involves mechanisms of calcium-induced signal transduction in brain, focusing on calmodulin-mediated enzymes. We have focused attention on the regulation of calmodulin-dependent protein phosphatase, and calcineurin. The role of phosphatases in cellular regulation is emerging as an exciting area of research, with implications for cell growth, signaling, and immune system regulation. We have found that calcineurin interacts with Bcl-2, and this interaction may play a role in apoptosis. Current attention is focused on identification of substrates for calcineurin, with an emphasis on cytoskeletal proteins, such as tau protein, which is highly phosphorylated in Alzheimer's disease. We have developed several in vitro and in vivo transgenic approaches for determination of changes in neuronal function caused by expression of specific tau mutant forms.

The second major area of the lab is the isolation and characterization of novel, neuron-specific genes, with emphasis on those involved in neurotoxic actions of various agents. We have used subtractive hybridization techniques coupled with selective neuronal ablation via neurotoxicant treatment to isolate gene products that are enriched in neurons sensitive to various toxicants. This approach has been applied towards understanding the molecular basis for the selective nature of organotin toxicity and has resulted in the isolation and sequencing of a novel cDNA, which may encode a protein involved in the molecular basis of neurotoxicity. The protein encoded by this cDNA has been identified and named stannin. We have found that stannin expressed in selective cells, and that it is located on human and mouse chromosome 16. This highly conserved protein may induce apoptosis via interactions with other proteins.

The third focus of my activities is the supervision of the Core Facilities at Penn State, College of Medicine. These labs provide state-of-the-art facilities for protein and DNA sequencing, Peptide and DNA synthesis, image analysis, and production of transgenic animals for disease models. These services are available for use on student thesis research projects and by faculty.
Publications
1. Billingsley ML. Druggable targets and targeted drugs: enhancing the development of new therapeutics. Pharmacology. 2008; 82(4):239-44.
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2. Billingsley ML, Washko M. Maximizing state and federal spending while minimizing conflicts. Nat Biotechnol. 2006 Dec; 24(12):1473-4.
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3. Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA, Veglia G. Functional and structural properties of stannin: roles in cellular growth, selective toxicity, and mitochondrial responses to injury. J Cell Biochem. 2006 May 15; 98(2):243-50.
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4. Reese BE, Krissinger D, Yun JK, Billingsley ML. Elucidation of stannin function using microarray analysis: implications for cell cycle control. Gene Expr. 2006; 13(1):41-52.
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5. Davidson CE, Reese BE, Billingsley ML, Yun JK. The protein stannin binds 14-3-3zeta and modulates mitogen-activated protein kinase signaling. Brain Res Mol Brain Res. 2005 Aug 18; 138(2):256-63.
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6. Reese BE, Davidson C, Billingsley ML, Yun J. Protein kinase C epsilon regulates tumor necrosis factor-alpha-induced stannin gene expression. J Pharmacol Exp Ther. 2005 Jul; 314(1):61-9.
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7. Davidson CE, Reese BE, Billingsley ML, Yun JK. Stannin, a protein that localizes to the mitochondria and sensitizes NIH-3T3 cells to trimethyltin and dimethyltin toxicity. Mol Pharmacol. 2004 Oct; 66(4):855-63.
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8. Erin N, Billingsley ML. Domoic acid enhances Bcl-2-calcineurin-inositol-1,4,5-trisphosphate receptor interactions and delayed neuronal death in rat brain slices. Brain Res. 2004 Jul 16; 1014(1-2):45-52.
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9. Erin N, Bronson SK, Billingsley ML. Calcium-dependent interaction of calcineurin with Bcl-2 in neuronal tissue. Neuroscience. 2003; 117(3):541-55.
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10. Erin N, Lehman RA, Boyer PJ, Billingsley ML. In vitro hypoxia and excitotoxicity in human brain induce calcineurin-Bcl-2 interactions. Neuroscience. 2003; 117(3):557-65.
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11. Pizoli CE, Jinnah HA, Billingsley ML, Hess EJ. Abnormal cerebellar signaling induces dystonia in mice. J Neurosci. 2002 Sep 1; 22(17):7825-33.
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12. Zhang J, Billingsley ML, Kincaid RL, Siraganian RP. Phosphorylation of Syk activation loop tyrosines is essential for Syk function. An in vivo study using a specific anti-Syk activation loop phosphotyrosine antibody. J Biol Chem. 2000 Nov 10; 275(45):35442-7.
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13. McGarrity TJ, Peiffer LP, Billingsley ML. Overexpression of epidermal growth factor receptor in Peutz-Jeghers syndrome. Dig Dis Sci. 1999 Jun; 44(6):1136-41.
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14. Garver TD, Kincaid RL, Conn RA, Billingsley ML. Reduction of calcineurin activity in brain by antisense oligonucleotides leads to persistent phosphorylation of tau protein at Thr181 and Thr231. Mol Pharmacol. 1999 Apr; 55(4):632-41.
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15. Billingsley ML, Thompson TA. Transfection of Mammalian cells in vitro: use in analysis of neuronal damage. Methods Mol Med. 1999; 22:99-103.
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16. Burkhart KK, Beard DC, Lehman RA, Billingsley ML. Alterations in tau phosphorylation in rat and human neocortical brain slices following hypoxia and glucose deprivation. Exp Neurol. 1998 Dec; 154(2):464-72.
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17. Dejneka NS, Polavarapu R, Deng X, Martin-DeLeon PA, Billingsley ML. Chromosomal localization and characterization of the stannin (Snn) gene. Mamm Genome. 1998 Jul; 9(7):556-64.
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18. Dejneka NS, Patanow CM, Polavarapu R, Toggas SM, Krady JK, Billingsley ML. Localization and characterization of stannin: relationship to cellular sensitivity to organotin compounds. Neurochem Int. 1997 Dec; 31(6):801-15.
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19. Billingsley ML, Kincaid RL. Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J. 1997 May 1; 323 ( Pt 3):577-91.
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20. Patanow CM, Day JR, Billingsley ML. Alterations in hippocampal expression of SNAP-25, GAP-43, stannin and glial fibrillary acidic protein following mechanical and trimethyltin-induced injury in the rat. Neuroscience. 1997 Jan; 76(1):187-202.
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21. Garver TD, Lehman RA, Billingsley ML. Microtubule assembly competence analysis of freshly-biopsied human tau, dephosphorylated tau, and Alzheimer tau. J Neurosci Res. 1996 Apr 1; 44(1):12-20.
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22. Thompson TA, Lewis JM, Dejneka NS, Severs WB, Polavarapu R, Billingsley ML. Induction of apoptosis by organotin compounds in vitro: neuronal protection with antisense oligonucleotides directed against stannin. J Pharmacol Exp Ther. 1996 Mar; 276(3):1201-16.
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23. Ogilvie P, Schilling K, Billingsley ML, Schmidt HH. Induction and variants of neuronal nitric oxide synthase type I during synaptogenesis. FASEB J. 1995 Jun; 9(9):799-806.
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24. Britt AM, Burkhart KK, Billingsley ML. Reversal of toxicity using avidin-based hemoperfusion: a model system in rats using biotinylated melittin. Pharmacology. 1995 May; 50(5):307-12.
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25. Garver TD, Oyler GA, Harris KA, Polavarapu R, Damuni Z, Lehman RA, Billingsley ML. Tau phosphorylation in brain slices: pharmacological evidence for convergent effects of protein phosphatases on tau and mitogen-activated protein kinase. Mol Pharmacol. 1995 Apr; 47(4):745-56.
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26. McLemore GL, Billingsley ML, Severs WB. Cardiac noradrenergic mechanisms mediate GABA-enhanced ouabain cardiotoxicity. Pharmacology. 1994 Dec; 49(6):343-50.
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27. Garver TD, Harris KA, Lehman RA, Lee VM, Trojanowski JQ, Billingsley ML. Tau phosphorylation in human, primate, and rat brain: evidence that a pool of tau is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro. J Neurochem. 1994 Dec; 63(6):2279-87.
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28. Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O'Connor M, Trojanowski JQ, Lee VM. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau. Neuron. 1994 Oct; 13(4):989-1002.
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29. Burkhart KK, Beard D, Billingsley ML. Enhanced elimination of biotinylated antibodies by avidin-based hemoperfusion in rats. J Pharmacol Exp Ther. 1994 Jul; 270(1):356-61.
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30. Billingsley ML, Ellis C, Kincaid RL, Martin J, Schmidt ML, Lee VM, Trojanowski JQ. Calcineurin immunoreactivity in Alzheimer's disease. Exp Neurol. 1994 Apr; 126(2):178-84.
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31. Gannon MN, Akompong T, Billingsley ML, McEwen BS. Adrenalectomy-induced alterations of calmodulin-dependent hippocampal adenylate cyclase activity: role of guanine nucleotide-binding proteins. Endocrinology. 1994 Feb; 134(2):853-7.
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32. McLemore GL, Billingsley ML, Severs WB. Ouabain cardiotoxicity is enhanced by GABA in anesthetized rats. Pharmacology. 1993 Aug; 47(2):126-34.
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33. Toggas SM, Krady JK, Thompson TA, Billingsley ML. Molecular mechanisms of selective neurotoxicants: studies on organotin compounds. Ann N Y Acad Sci. 1993 May 28; 679:157-77.
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34. Harris KA, Oyler GA, Doolittle GM, Vincent I, Lehman RA, Kincaid RL, Billingsley ML. Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. Ann Neurol. 1993 Jan; 33(1):77-87.
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35. Toggas SM, Krady JK, Billingsley ML. Molecular neurotoxicology of trimethyltin: identification of stannin, a novel protein expressed in trimethyltin-sensitive cells. Mol Pharmacol. 1992 Jul; 42(1):44-56.
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36. Lynch CJ, McCall KM, Billingsley ML, Bohlen LM, Hreniuk SP, Martin LF, Witters LA, Vannucci SJ. Pyruvate carboxylase in genetic obesity. Am J Physiol. 1992 May; 262(5 Pt 1):E608-18.
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37. Oyler GA, Polli JW, Higgins GA, Wilson MC, Billingsley ML. Distribution and expression of SNAP-25 immunoreactivity in rat brain, rat PC-12 cells and human SMS-KCNR neuroblastoma cells. Brain Res Dev Brain Res. 1992 Feb 21; 65(2):133-46.
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38. Kincaid RL, Balaban CD, Billingsley ML. Regional and developmental expression of calmodulin-dependent cyclic nucleotide phosphodiesterase in rat brain. Adv Second Messenger Phosphoprotein Res. 1992; 25:111-22.
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39. Polli JW, Billingsley ML, Kincaid RL. Expression of the calmodulin-dependent protein phosphatase, calcineurin, in rat brain: developmental patterns and the role of nigrostriatal innervation. Brain Res Dev Brain Res. 1991 Nov 19; 63(1-2):105-19.
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40. Polli JW, Kincaid RL, Torris J, Billingsley ML. Expression of calmodulin-dependent enzymes in developing rat striatum is not affected by perturbation of dopaminergic systems. Synapse. 1991 Oct; 9(2):136-43.
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41. McGarrity TJ, Peiffer LP, Billingsley ML. Interspecies comparison of calmodulin binding proteins throughout the gastrointestinal tract: comparison with human colon adenomas and adenocarcinomas. Gut. 1991 Oct; 32(10):1121-6.
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42. Leitzel K, Bryce W, Tomita J, Manderino G, Tribby I, Thomason A, Billingsley M, Podczaski E, Harvey H, Bartholomew M, et al. Elevated plasma platelet-derived growth factor B-chain levels in cancer patients. Cancer Res. 1991 Aug 15; 51(16):4149-54.
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43. Oyler GA, Polli JW, Wilson MC, Billingsley ML. Developmental expression of the 25-kDa synaptosomal-associated protein (SNAP-25) in rat brain. Proc Natl Acad Sci U S A. 1991 Jun 15; 88(12):5247-51.
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44. Polli JW, Billingsley ML. Preparation, characterization and biological properties of biotinylated derivatives of calmodulin. Biochem J. 1991 May 1; 275 ( Pt 3):733-43.
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45. Krady JK, Oyler GA, Balaban CD, Billingsley ML. Use of avidin-biotin subtractive hybridization to characterize mRNA common to neurons destroyed by the selective neurotoxicant trimethyltin. Brain Res Mol Brain Res. 1990 May; 7(4):287-97.
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46. Billingsley ML, Polli JW, Balaban CD, Kincaid RL. Developmental expression of calmodulin-dependent cyclic nucleotide phosphodiesterase in rat brain. Brain Res Dev Brain Res. 1990 May 1; 53(2):253-63.
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47. Polli JW, Patanow CM, Billingsley ML. Developmental expression of neuronal calmodulin-binding proteins in rat brain. Brain Res Dev Brain Res. 1990 Apr 1; 53(1):62-70.
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48. Billingsley ML, Polli JW, Pennypacker KR, Kincaid RL. Identification of calmodulin-binding proteins. Methods Enzymol. 1990; 184:451-67.
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49. Oyler GA, Higgins GA, Hart RA, Battenberg E, Billingsley M, Bloom FE, Wilson MC. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol. 1989 Dec; 109(6 Pt 1):3039-52.
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50. Balaban CD, Billingsley ML, Kincaid RL. Evidence for transsynaptic regulation of calmodulin-dependent cyclic nucleotide phosphodiesterase in cerebellar Purkinje cells. J Neurosci. 1989 Jul; 9(7):2374-81.
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51. Pennypacker KR, Kuhn DM, Billingsley ML. Changes in expression of tyrosine hydroxylase immunoreactivity in human SMS-KCNR neuroblastoma following retinoic acid or phorbol ester-induced differentiation. Brain Res Mol Brain Res. 1989 Jun; 5(4):251-8.
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52. Pennypacker KR, Kincaid RL, Polli JW, Billingsley ML. Expression of calmodulin-dependent phosphodiesterase, calmodulin-dependent protein phosphatase, and other calmodulin-binding proteins in human SMS-KCNR neuroblastoma cells. J Neurochem. 1989 May; 52(5):1438-48.
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53. Balaban CD, O'Callaghan JP, Billingsley ML. Trimethyltin-induced neuronal damage in the rat brain: comparative studies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins. Neuroscience. 1988 Jul; 26(1):337-61.
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54. Pennypacker KR, Kyritsis A, Chader GJ, Billingsley ML. Calmodulin-binding proteins in human Y-79 retinoblastoma and HTB-14 glioma cell lines. J Neurochem. 1988 May; 50(5):1648-54.
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55. Kincaid RL, Billingsley ML, Vaughan M. Preparation of fluorescent, cross-linking, and biotinylated calmodulin derivatives and their use in studies of calmodulin-activated phosphodiesterase and protein phosphatase. Methods Enzymol. 1988; 159:605-26.
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56. Kincaid RL, Takayama H, Billingsley ML, Sitkovsky MV. Differential expression of calmodulin-binding proteins in B, T lymphocytes and thymocytes. Nature. 1987 Nov 12-18; 330(6144):176-8.
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57. Kincaid RL, Balaban CD, Billingsley ML. Differential localization of calmodulin-dependent enzymes in rat brain: evidence for selective expression of cyclic nucleotide phosphodiesterase in specific neurons. Proc Natl Acad Sci U S A. 1987 Feb; 84(4):1118-22.
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58. Kuhn DM, Billingsley ML. Tyrosine hydroxylase: purification from PC-12 cells, characterization and production of antibodies. Neurochem Int. 1987; 11(4):463-75.
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59. Billingsley ML, Balaban CD, Berresheim U, Kuhn DM. Comparative studies on the distribution of protein-o-carboxylmethyltransferase and tyrosine hydroxylase in rat brain by immunocytochemistry. Neurochem Int. 1986; 8(2):255-65.
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60. Kincaid RL, Balaban CD, Billingsley ML. Regulated expression of calmodulin-dependent cyclic nucleotide phosphodiesterase in the central nervous system. J Cyclic Nucleotide Protein Phosphor Res. 1986-1987; 11(7):473-86.
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61. Billingsley ML, Balaban CD. Protein-O-carboxylmethyltransferase in the rat brain: high regional levels in the substantia nigra, locus coeruleus and paraventricular nucleus. Brain Res. 1985 Dec 9; 358(1-2):96-103.
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62. Billingsley ML, Pennypacker KR, Hoover CG, Brigati DJ, Kincaid RL. A rapid and sensitive method for detection and quantification of calcineurin and calmodulin-binding proteins using biotinylated calmodulin. Proc Natl Acad Sci U S A. 1985 Nov; 82(22):7585-9.
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63. Billingsley ML, Kincaid RL, Lovenberg W. Stoichiometric methylation of calcineurin by protein carboxyl O-methyltransferase and its effects on calmodulin-stimulated phosphatase activity. Proc Natl Acad Sci U S A. 1985 Sep; 82(17):5612-6.
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64. Billingsley ML, Kim S, Kuhn DM. Immunohistochemical localization of protein-O-carboxylmethyltransferase in rat brain neurons. Neuroscience. 1985 May; 15(1):159-71.
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65. Billingsley ML, Velletri PA, Lovenberg W, Kuhn D, Goldenring JR, DeLorenzo RJ. Is Ca2+-calmodulin-dependent protein phosphorylation in rat brain modulated by carboxylmethylation? J Neurochem. 1985 May; 44(5):1442-50.
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66. Billingsley ML, Lovenberg W. Protein carboxylmethylation and nervous system function. Neurochem Int. 1985; 7(4):575-87.
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67. Billingsley M, Kuhn D, Velletri PA, Kincaid R, Lovenberg W. Carboxylmethylation of phosphodiesterase attenuates its activation by ca2+-calmodulin. J Biol Chem. 1984 May 25; 259(10):6630-5.
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68. Hanbauer I, Memo M, Billingsley M. Role of calmodulin in the regulation of dopamine receptor function. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984; 17:521-7.
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69. Hurst JH, Guchhait RB, Billingsley ML, Stolk JM, Lovenberg W. Phenylethanolamine N-methyltransferase: notes on its purification from bovine adrenal medulla and separation from protein carboxymethyltransferase. Biochem Biophys Res Commun. 1983 May 16; 112(3):1061-8.
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70. Billingsley ML, Velletri PA, Roth RH, DeLorenzo RJ. Carboxylmethylation of calmodulin inhibits calmodulin-dependent phosphorylation in rat brain membranes and cytosol. J Biol Chem. 1983 May 10; 258(9):5352-7.
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71. Billingsley ML, Roth RH. Dopamine agonists stimulate protein carboxylmethylation in striatal synaptosomes. J Pharmacol Exp Ther. 1982 Dec; 223(3):681-8.
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72. Billingsley ML, Straw JA, Mandel HG. Glial DNA synthesis and cell proliferation in the lesioned frontal cortex of the rat. Brain Res. 1982 Sep 16; 247(2):325-34.
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73. Billingsley ML, Mandel HG. Effects of DNA synthesis inhibitors on post-traumatic glial cell proliferation. J Pharmacol Exp Ther. 1982 Sep; 222(3):765-70.
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74. Billingsley ML, Suria A. Effects of peripherally administered GABA and other amino acids on cardiopulmonary responses in anesthetized rats and dogs. Arch Int Pharmacodyn Ther. 1982 Jan; 255(1):131-40.
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Keyword
Last Name
Institution
    
 
 
 
Keywords   
Neuropeptides
Brain
tau Proteins
Calmodulin
Calcineurin
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Co-Authors  
Bronson, Sarah
Lynch, Christopher
Mcgarrity, Thomas
Severs, Walter
Yun, Jong
See all (6) people
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