In the years since my laboratory at the NIDA IRP identified the sigma-1 receptor (Sig-1R) in 1982, many preclinical studies have shown that Sig-1Rs and associated ligands are involved in stroke, amnesia, depression, cancer, Alzheimers disease, pain, and psychostimulant addiction. We found here that Sig-1Rs reside at an intracellular organelle called the endoplasmic reticulum (ER) that is responsible for the synthesis of most of proteins in the cell. More specifically, Sig-1Rs localize at a particular subdomain at the ER membrane that directly faces and contacts another intracellular organelle called mitochondrion which produces energy for the cell. Sig-1Rs thus play a very important role in the cell by directly communicating the well-being of the protein synthesis machinery to the energy-producing organalle in the cell. For example, Sig-1Rs regulate calcium transfer and lipid metabolism between the ER and mitochondrion and are thus involved in many cellular processes critical for the proper functioning of the living system. Inasmuch as Sig-1Rs are molecular chaperones that regulate the functionality of proteins by maintaining them at a proper three-domensional configuration, we are examining what proteins, in addition to the IP3 receptors that we have so far discovered, might be chaperoned by Sig-1Rs. In doing so, we might have a better understanding of how this molecular chaperone, the Sig-1R, may play a role in so many diseases. In this fiscal year we found that the Sig-1R can translocate to the plasma membrane to interact with potassium channel Kv1.2 to attenuate the intrinsic excitability of neurons that in turn enhances animal's behavioral responses to cocaine. we also found that Sig-1R can participate in the degradation of misfolded proteins to fight against protein misfolding diseases.

Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2013
Total Cost
$1,636,871
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
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Country
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Lewis, Abasha; Hayashi, Teruo; Su, Tsung-Ping et al. (2014) Bcl-2 family in inter-organelle modulation of calcium signaling; roles in bioenergetics and cell survival. J Bioenerg Biomembr 46:1-15
Kourrich, Saïd; Hayashi, Teruo; Chuang, Jian-Ying et al. (2013) Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152:236-47
Hayashi, Teruo; Rizzuto, Rosario; Hajnoczky, Gyorgy et al. (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81-8
Su, Tsung-Ping; Hayashi, Teruo; Vaupel, D Bruce (2009) When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor. Sci Signal 2:pe12
Maurice, Tangui; Su, Tsung-Ping (2009) The pharmacology of sigma-1 receptors. Pharmacol Ther 124:195-206
Lee, Chun-Ting; Chen, Jia; Hayashi, Teruo et al. (2008) A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med 5:e117
Hayashi, Teruo; Su, Tsung-Ping (2008) An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma 1 receptor ligand. Expert Opin Ther Targets 12:45-58