Manasi Malik

Program: Molecular Cell Biology

Current advisor: Sarah England, PhD

Undergraduate university: University of Kentucky

Research summary
The hormone oxytocin is commonly prescribed during childbirth to initiate uterine contractions and prevent post-partum hemorrhage and may have utility in managing autism and other behavioral traits. Oxytocin acts by binding to the OXTR to activate Gq-coupled signaling and calcium flux, which is followed by desensitization and internalization mediated by β-arrestin. Variants of unknown significance in the OXTR gene are prevalent in many populations, and may affect response to endogenous and exogenous oxytocin. To test this idea in vitro, I identified the 11 OXTR genetic variants that had the highest worldwide prevalence. I performed a functional screen on these variants to identify five – V45L, P108A, L206V, V281M, and E339K – that altered calcium flux or β-arrestin recruitment. When I quantified the effects of these five OXTR variants on total and membrane receptors, I found that the variants P108A and L206V increased OXTR localization to the cell membrane, whereas V281M and E339K caused OXTR to be retained inside the cell. When I compared how each variant affected OXTR activation, internalization, and desensitization, I found that three of the five induced signaling bias, a term used to describe preferential activation of one signaling pathway over another. Specifically, V45L and P108A did not alter OXTR activation but did impair internalization and desensitization. In contrast, V281M decreased OXTR activation but had no effect on internalization and desensitization. My results thus far show that missense variants in OXTR affect oxytocin response by altering receptor trafficking to the cell membrane and by disrupting the balance between OXTR activation and desensitization.

Graduate publications
Fang Y, Malik M, England SK, Imoukhuede PI. 2022 Absolute Quantification of Plasma Membrane Receptors Via Quantitative Flow Cytometry. Methods Mol Biol, 2475():61-77.

Malik M, Fang Y, Wakle-Prabagaran M, Roh M, Prifti K, Frolova AI, Imoukhuede PI, England SK. 2022 Pharmacological chaperones for the oxytocin receptor increase oxytocin responsiveness in myometrial cells. J Biol Chem, 298(3):101646.

Malik M, Ward MD, Fang Y, Porter JR, Zimmerman MI, Koelblen T, Roh M, Frolova AI, Burris TP, Bowman GR, Imoukhuede PI, England SK. 2021 Naturally Occurring Genetic Variants in the Oxytocin Receptor Alter Receptor Signaling Profiles. ACS Pharmacol Transl Sci, 4(5):1543-55.

Ma X, Zhao P, Wakle-Prabagaran M, Amazu C, Malik M, Wu W, Wang H, Wang Y, England SK. 2020 Microelectrode array analysis of mouse uterine smooth muscle electrical activity. Biol Reprod, 102(4):935-942.

Malik M, Shi N, Lee G, Reinl E, Raghuraman N, England S. (2018) Effect of genetic variants on oxytocin receptor function. Keystone Symposium: GPCR Structure and Function, Santa Fe, NM, Abstract.

Malik M, Shi N, Lee G, Reinl E, Raghuraman N, England S. (2018) Functional impact of oxytocin receptor coding variants on oxytocin responsiveness. Institute of Clinical and Translational Sciences Symposium, St. Louis, MO, Abstract.