This proposal describes a 5-year training program for the development of an independent investigator in volatile anesthetic mechanisms. The principal investigator is a faculty member in the Department of Anesthesia, Harvard Medical School, with a background in electrophysiology, who will acquire new knowledge and skills in neuroscience and pharmacology sufficient to lead his own independent research program. Work will be conducted in the Mallinckrodt Pharmacology Research Unit at Massachussets General Hospital which focuses on volatile anesthetic mechanisms.
Our SPECIFIC AIMS wil test the novel hypothesis that volatile anesthetics potentiate TASK-3 function indirectly by inhibition of basal or agonst-mediated Galpha-q protein coupled receptor (GqPCR) activity. The TASK-3 tandem pore potassium channel is a volatile anesthetic-potentiated and pH- and hypoxia-inhibited ion channel. TASK-3 is widely expressed in the central nervous system and in peripheral tissue and has a role in chemosensing in a variety of cell types, including those involved in regulation of breathing. TASK-3 function is also inhibited by GqPCR activation. GqPCRs in the CNS regulate memory, wakefulness, and consciousness and peripherally are important regulators of smooth muscle tone. The function of many GqPCRs are inhibited by volatile anesthetics. To test our hypothesis we will use two-electrode voltage clamp of Xenopus oocytes or Ussing Chamber studies of Fischer Rat Thyroid cells heterologously expressing TASK-3 channels and ml or m3 GqPCRs and Galpha-q protein. We will also employ the excised patch-clamp method, and several molecular biology techniques including RNA interference and site-directed mutagenesis. LONG TERM GOALS: This project will clairfy the molecular mechanism by which volatile anesthetics potentiate TASK channels.
This work will help establish principles to guide development of safer anesthetic drugs that do not effect breathing and further elucidate the mechanism by which these drugs induce anesthesia.
|Ge, Rile; Pejo, Ervin; Gallin, Hilary et al. (2014) The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol. Anesth Analg 118:563-7|
|Shanmugasundararaj, Sivananthaperumal; Zhou, Xiaojuan; Neunzig, Jens et al. (2013) Carboetomidate: an analog of etomidate that interacts weakly with 11Î²-hydroxylase. Anesth Analg 116:1249-56|
|Wong, Kin Foon Kevin; Gong, Jen J; Cotten, Joseph F et al. (2013) Assessing the effects of pharmacological agents on respiratory dynamics using time-series modeling. IEEE Trans Biomed Eng 60:1118-25|
|Cotten, Joseph F (2013) TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore potassium channel antagonists stimulate breathing in isoflurane-anesthetized rats. Anesth Analg 116:810-6|
|Pejo, Ervin; Feng, Yan; Chao, Wei et al. (2012) Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia. Crit Care Med 40:187-92|
|Pejo, Ervin; Ge, Rile; Banacos, Natalie et al. (2012) Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats. Anesthesiology 116:1057-65|
|Conway, Kevin E; Cotten, Joseph F (2012) Covalent modification of a volatile anesthetic regulatory site activates TASK-3 (KCNK9) tandem-pore potassium channels. Mol Pharmacol 81:393-400|
|Solt, Ken; Cotten, Joseph F; Cimenser, Aylin et al. (2011) Methylphenidate actively induces emergence from general anesthesia. Anesthesiology 115:791-803|
|Gong, Jen J; Wong, Kin Foon Kevin; Cotten, Joseph F et al. (2011) Correcting for serial dependence in studies of respiratory dynamics. Conf Proc IEEE Eng Med Biol Soc 2011:1721-4|
|Cotten, Joseph F; Le Ge, Ri; Banacos, Natalie et al. (2011) Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function. Anesthesiology 115:764-73|