Associate Professor

Associate Research Scientist at Yale University
NARSAD and AHA Postdoctoral Fellow, Yale University
Ph.D., University of Western Ontario
B.S., Bogazici University (Formerly known as Robert College)

E-mailKilicFusun@uams.edu
Office:  (501)526-6488 – Biomedical Research Center B405D
Lab:  (501)686-5194 – Biomedical Research Center B410
FAX:  (501)686-8169

Serotonin and serotonin transporter protein.

Serotonin (5-HT) – a neurotransmitter, a vasoconstrictor compound that also acts as a mitogen, promotes cell division, mitosis, and a developmental signal early in embryogenesis.  The extracellular concentration of this multifunctional signaling molecule is associated with various diseases and must be regulated constantly by a single-gene product 5-HT transporter, SERT which is expressed on the plasma membrane of platelet, placenta and presynaptic terminals.  The 5-HT uptake capacity of the platelets depends on the number of SERT molecules on the plasma membrane.  Using a strategy of progressive integration, i.e., clinical (placentas, blood samples from term diabetic, episodic hypertensive and healthy/control subjects); and preclinical (peripheral 5-HT knock out TPH1-/-, SERT-/- and control mice), we explore to delineate the sequence of molecular events in the mechanism by which 5-HT- signaling facilitates the membrane trafficking, association with other proteins as well as post-translational modifications of SERT and how they are altered at pathophysiological conditions.

Through collaboration with UAMS-OB/GYN Department, we have access to maternal, cord blood and placenta of healthy and diabetes-associated pregnant subjects. We prepare trophoblast and platelets from these tissues and study the impact of diabetes on placenta and embryo (Basnet et al., J.Preg.Child Health 2015). We are interested in the post translational modification of SERT in placenta and platelet and the impact of diabetes, high glucose and lack of insulin signaling on these modifications.  We showed that in diabetes, placental SERT molecules cannot associate in oligomeric form (Unal et al., J. Neurochem. 2007) due to the defect in the ERp44-SERT dissociation (Freyaldenhoven et al., JBC, 2012; Li et al., PNAS 2014) and N-glycosylation (Ozaslan et al, JBC 2003; Li et al., PNAS, 2014). Interestingly in pregnancy associated with diabetes, insulin receptor in placenta but not in platelet is not phosphorylated (Li et al., JBC 2016); please click the following links for further information on our diabetes in pregnancy research and other serotonin-related studies;

(http://www.uamshealth.com/news/?id=5351&sid=1&nid=10115&cid=6).

A new Keystone Meeting that we are organizing on Serotonin outside the brain:

(http://uamshealth.com/news/2016/05/06/kilic-chosen-to-initiate-conference-on-serotonin-outside-the-brain).

 

Selected Publications

Joo JH, Wang B, Frankel E, Ge L, Xu L, Iyengar R, Li-Harms X, Wright C, Shaw TI, Lindsten T, Green DR, Peng J, Hendershot LM, Kilic F, Sze JY, Audhya A, Kundu M. The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. Mol Cell. 2016. 62(6):982. doi: 10.1016/j.molcel.2016.05.030. [Abstract]

Li Y, Cooper A, Odibo IN, Ahmed A, Murphy P, Koonce R, Dajani NK, Lowery CL, Roberts DJ, Maroteaux L, Kilic F. Discrepancy in insulin regulation between GDM-platelets and -placenta. J. Biol Chem. 2016. 291(18):9657-65. doi: 10.1074/jbc.M116.713693. PMID: 26921319  [Abstract]

Li Y, Hadden C, Cooper A, Ahmed A, Wu H, Lupashin VV, Mayeux PR, Kilic F. Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability. NPG-Sci Rep. 2016. 6:22747. DOI: 10.1038/srep22747. [Abstract]

Basnet, K., Bentley-Lewis, R., Wexler, D., Kilic, F., and Roberts, D.J. Intervillous thrombi are increased in placentas from pregnancies complicated by diabetes. Journal of Pregnancy & Child Health 2015. Dec 15.. [Abstract]

Li Y, Hadden C, Singh P, Mercado CP, Murphy P, Dajani NK, Lowery CL, Roberts DJ, Maroteaux L,Kilic F. GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proc. Natl. Acad. Sci USA. 2014. 111(52):E5697-705. doi: 10.1073/pnas. [Abstract]

Fraer M, Kilic F. Serotonin: A Different Player in Hypertension-Associated Thrombosis. Hypertension. 2015. Mar 9. pii: Hypertension-AHA.114.05061. [Abstract]

Ziu, E., Hadden, C., Li, Y., Lowery III, CL., Singh, P., Ucer, SS., Mercado, C., Gu, HH., Kilic, F. Effect of serotonin on platelet function in cocaine exposed blood. NPG-Sci. Rep. 2014. 4, 5945. DOI: 10.1038/srep05945.  [Abstract]

Mercado CP, Quintero MV, Li Y, Singh P, Byrd AK, Talabnin K, Ishihara M, Azadi P, Rusch NJ, Kuberan B, Maroteaux L, Kilic F. A serotonin-induced N-glycan switch regulates platelet aggregation. NPG-Sci. Rep. 2013 3, 2795. DOI: 10.1038/srep02795.  [Abstract]

Mercado CP., Byrum S., Beggs ML., Ziu E., Raj VR., Haun RS., Kilic F. Impact of Elevated Plasma Serotonin on Global Gene Expression of Murine Megakaryocytes PLoSONE, 2013. 8(8):e72580. PMID: 24013211.  [Abstract]

Singh P., Fletcher TW., Li Y., Rusch NJ., Kilic F. Serotonin uptake rates in platelets from angiotension II-induced hypertensive mice. Health, Special issue on Hypertension and Cardiovascular Diseases 2013. 5(4A) 31-39. DOI: 10.4236/health.  [Abstract]

Freyaldenhoven, S., Li, Y., Kocabas, A.M., Ziu, E., Ucer, S., Ramanagoudr-Bhojappa, R., Miller, G.P., and Kilic, F. “The Role of ERp44 on the Maturation of Serotonin Transporter proteins. J. Biol. Chem. 2012. 287: 17801-17811.  [Abstract]

Ziu, E., Freyaldenhoven, S., Mercado, C.P., Ahmed, B.A., Preeti, P., Lensing, S., Ware, J., and Kilic, F. Down-regulation of the Serotonin Transporter in hyperreactive platelets counteracts the pro-thrombotic effect of serotonin. 2012. J. Mol. Cell. Cardiol52:1112-21. PMID: 22366712.PMC3327821.  [Abstract]

Mercado, C., Ziu, E., Kilic, F. Communication between 5-HT and small GTPases Current Opinion in Pharmacology.  2011. 11:23-28. NIHMS271607.  [Abstract]

Mercado, C., and Kilic, F. “Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels.”   Molecular Interventions. 2010. 10:231-241. PMID: 20729489 PMC20729489.  [Abstract]

Ahmed, B., Bukhari IA, Jeffus BC, Harney JT, Thyparambil S, Ziu E, Fraer  M, Rusch NJ, Zimniak P, Lupashin V, Tang D, Kilic F.: The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network.  PLoSONE, 2009. 4:e4730. PMID:19270731. PMC2648896.  [Abstract]

Ahmed, BA., Jeffus, B., Harney, JT., Bukhari, IS., Unal, R., Lupashin, VV.,  van der Sluijs, P., and Kilic, F. Serotonin transamidates Rab4 and facilitates binding to the C-terminus of hSERT. J  Biol Chem. 2008. 283:9388-9398. PMID: 18227069.  [Abstract]

Brenner, B., Harney, JT., Ahmed, BA., Jeffus, BC., Unal, R., Mehta J.L., and Kilic, F. Plasma serotonin level and the platelet serotonin transporter. J. Neurochem. 2007. 102:206-216. PMID:17506858.  [Abstract]

Unal, R., Ahmed, BA., Jeffus, BA., Harney, J.T., Lyle, CS., Wu, Y-K. Chambers, TC., Reece, EA, and Kilic, F. At diabetes-like concentration, glucose down-regulates the placental serotonin transport system by abolishing its homo-oligomerization. J. Neurochem. 2007. 101:937-48. PMID: 17355243.  [Abstract]

Ozaslan, D., Wang, S., Ahmed, B., Bene, A., Kocabas, AM., and Kilic, F. Glycosyl Modification Facilitates Homo- and Hetero-Oligomerization of Serotonin Transporter. A Specific Role for the Sialic Acid Residues. J. Biol. Chem. 2003. 278:43991-44000. PMID: 12944413.  [Abstract]

Kocabas, AM, Rudnick G, Kilic F. Functional consequences of homo- but not hetero-oligomerization between transporters for the biogenic amine neurotransmitters. J. Neurochem. 2003. 85:1513-1520. PMID: 12787070.  [Abstract]

Kilic F, Murphy D, Rudnick G. A human serotonin trans­porter mutation cau­ses constitutive activation of trans­port activity.  Mol.  Pharm. 2003. 64:4-12. PMID: 12869649.  [Abstract]

Kilic F, Rudnick G.  Oligomerization of the serotonin transporter and its functional consequences. Proc. Natl. Acad. Sci USA 2000. 97:3106-3111. PMID: 10716733.  [Abstract]