This project is designed to enhance the PI's research capability and the skills and interests of our undergraduate and master's students in neuroscience by having them to participate in the PI's ongoing research project in the endogenous cannabinoid system at The University of Texas at Brownsville (a primarily teaching institution with an academically diverse 93% Hispanic community). Cannabinoid, the bioactive component in marijuana and hashish, affects the brain by acting on the brain cannabinoid receptor (CB1R). Natural molecules that activate CB1R are endocannabinoids (eCBs). eCBs are increasingly recognized as critical signaling molecules in many neurobiological phenomena including synaptic plasticity, memory, reward learning, pain, neuroprotection, and addiction;all of which makes understanding the process of eCB-synthesis a matter of great importance. The PI has demonstrated that a key process to initiate the production of eCBs in the hippocampus is a release of calcium ions from the ryanodine receptor (RyR). The discovery was made by artificially-depolarizing neurons. Therefore, the goal of the present proposal is to identify physiological conditions and endogenous molecule(s) that activate RyR in hippocampal neurons for the production of eCBs. Ghrelin, an orexigenic brain peptide hormone, is selected for investigation. Why ghrelin? Because ghrelin and the ghrelin receptor are involved in reward-related memories in which eCBs are also involved. In addition, the PI's preliminary data suggest the activation of the ghrelin receptor stimulates protein kinase A (PKA), which is reported to enhance the function of RyR.
Specific Aims of this proposal are: 1) to determine the localization of the ghrelin receptor in the hippocampus, 2) to characterize cytoplasmic calcium dynamics and eCB-synthesis in response to ghrelin, and 3) to determine the extent to which ghrelin regulates hippocampal synaptic plasticity. Experiments are conducted in cultured hippocampal slices with the techniques of patch clamp recording, calcium imaging, immunohistochemistry, siRNA and eGFP transfection. eCBs and their regulation by calcium are topics of great interest to a wide range of biomedical scientists. Thus, the identification of physiological conditions that initiate the production of brain eCBs will provide a critical understanding for potent neuronal signaling systems of eCBs. The project also offers a valuable opportunity for students to obtain laboratory research experiences, which undoubtedly raise their awareness in public health and diseases, and aid them in establishing their professional careers in biomedical research.

Public Health Relevance

Endogenous cannabinoids (eCBs) are increasingly recognized as critical signaling molecules in many areas of the nervous system. They modulate important neurobiological phenomena in health and diseases such as memory and learning, reward and motivation, pain, and addiction. Thus, my research of investigating cellular and molecular mechanisms for the production of eCBs in the brain will provide a critical understanding of this powerful signaling system and help further the understanding of a number of fundamental and clinically-relevant biomedical issues.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-E (96))
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Sorensen, Roger
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University/Texas Brownsville & Southmost Coll
Internal Medicine/Medicine
Schools of Allied Health Profes
United States
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Murtuza, Mohammad I; Isokawa, Masako (2018) Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus. J Neurochem 144:58-67
Berrout, Liza; Isokawa, Masako (2018) Ghrelin upregulates the phosphorylation of the GluN2B subunit of the NMDA receptor by activating GHSR1a and Fyn in the rat hippocampus. Brain Res 1678:20-26
Isokawa, Masako (2016) Caffeine-Induced Suppression of GABAergic Inhibition and Calcium-Independent Metaplasticity. Neural Plast 2016:1239629
Muniz, Brandon G; Isokawa, Masako (2015) Ghrelin receptor activity amplifies hippocampal N-methyl-d-aspartate receptor-mediated postsynaptic currents and increases phosphorylation of the GluN1 subunit at Ser896 and Ser897. Eur J Neurosci 42:3045-53
Berrout, Liza; Isokawa, Masako (2012) Ghrelin promotes reorganization of dendritic spines in cultured rat hippocampal slices. Neurosci Lett 516:280-4
Isokawa, Masako (2012) Cellular signal mechanisms of reward-related plasticity in the hippocampus. Neural Plast 2012:945373
Cuellar, Jacquelynn N; Isokawa, Masako (2011) Ghrelin-induced activation of cAMP signal transduction and its negative regulation by endocannabinoids in the hippocampus. Neuropharmacology 60:842-51
Isokawa, Masako (2009) Time-dependent induction of CREB phosphorylation in the hippocampus by the endogenous cannabinoid. Neurosci Lett 457:53-7
Berrout, Jonathan; Isokawa, Masako (2009) Homeostatic and stimulus-induced coupling of the L-type Ca2+ channel to the ryanodine receptor in the hippocampal neuron in slices. Cell Calcium 46:30-8