Kiran Sapkota, PhD
Laboratory: Daniel T. Monaghan, PhD
University of Nebraska Medical Center (DRC 3054)
985800 Nebraska Medical Center
Omaha Nebraska, NE 68198-5800
Keywords: NMDA receptor pharmacology, NMDA receptor allosteric modulators, FLIPR- based high throughput screening, two-electrode voltage clamp (TEVC) electrophysiology, ketamine, schizophrenia, and electroencephalography.
- Study of N-methyl-D-aspartate receptors (NMDARs) subtypes specially GluN2C-2D-subtype in psychiatric disorders such as schizophrenia and autism
- Development and pharmacology of NMDAR allosteric modulators with potential application for neuropsychiatric disorders such as schizophrenia
- Mechanism of action of NMDAR allosteric modulators
- Use of NMDA receptor subtype selective modulators to study the role of specific receptor subtypes in nervous system function and CNS disorders
- Characterization and pharmacological study of NMDAR allosteric modulators:
Evidence from various studies strongly suggests the association of NMDA receptors with schizophrenia. Reduced NMDAR function, especially in GABAergic interneurons containing parvalbumin (PV), is one of the replicative factors involved in pathophysiology of schizophrenia. The primary goal of this project is to identify chemical compounds selectively potentiating the GluN2D subtype since these are expressed in PV-neurons. Identification of subunit-selective modulators for other subtypes also serve valuable tools for studying brain function under normal and pathological conditions. We are also interested in studying NMDA receptor signaling in astrocytes.
- Nakao K, Singh M, Sapkota K, Hagler B, Hunter R, Raman C, Hablitz JJ and Nakazawa K. Normalizing glycogen synthase kinase-3β activity in corticolimbic GABAergic neurons rescues abnormal gamma oscillation in an NMDA receptor hypofunction model of schizophrenia. 2020.
- Zhou YJ, Chen JM, Sapkota K, Long JY, Liao YJ, Jiang JJ, Liang BY, Wei JB, Zhou Y. Pananx notoginsengsaponins attenuate CCL2-induced cognitive deficits in rats via anti-inflammation and anti-apoptosis effects that involve suppressing over-activation of NMDA receptors. Biomedicine and Pharmacotherapy. 2020, 127:110139.
- Wang JX, Irvine MW, Burnell E, Sapkota K, Thatcher RJ, Li M, Simorowski N, Volianskis A, Gollingridge GL, Monaghan DT, Jane DE, Furukawa H. Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors. Nature Communication. 2020, 11:423.
- Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacology and Therapeutics. 205, 107426, 2020.
- Irvine MW*, Fang F*, Sapkota K*, Burnell E, Volianskis A, Costa BM, Culley G, Collingridge GL, Monaghan DT, Jane DE. Investigation of the structural requirements for N-Methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid. European Journal of Medicinal Chemistry. 2019, 164:471-498. *Equal contribution.
- Sapkota K, Dore K, Tang K, Irvine MW, Fang F, Burnell E, Malinow R, Jane DE, Monaghan DT. The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators. Biochemical Pharmacology. 2019, 159:140-153.
- Burnell E, Irvine MW, Fang F, Sapkota K, Jane DE, Monaghan DT. Positive and negative allosteric modulators of NMDA receptors; structure-activity relationships and mechanisms of action. Journal of Medicinal Chemistry. 2019, 62: 3-23.
- Chopra DA, Sapkota K, Irvine MW, Fang GL, Jane DE, Monaghan DT, Dravid S. A novel gating mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors. Scientific Reports. 2017; 7.
- Sapkota K, Irvine MW, Fang F, Burnell E, Bannister N, Volianskis A, Culley GR, Dravid SM, Collingridge GL, Jane DE, Monaghan DT. Mechanisms and properties of positive allosteric modulation of N-methyl-D-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives. Neuropharmacology. 2017; 125:64-79.
- Sapkota K, Mao Z, Synowicki P, Lieber D, Liu M, Ikezu T, Gautam V, Monaghan D. GluN2D N-methyl-D-aspartate subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine: implications for schizophrenia. Journal of Pharmacology and Experimental Therapeutics. 2016; 356:702-712.