My laboratory investigates complex neurobiological processes and how they are regulated through the cholinergic system. I focus on a class of modulators, lynx genes, which are important regulatory proteins over the cholinergic system. Lynx proteins act as molecular brakes, binding to nicotinic acetylcholine receptors of this system and modifying their function. We use a highly multidisciplinary approach through the generation of genetically engineered mouse lines and the characterization of such line by electrophysiological, behavioral, biochemical and microscopic techniques. These investigations have been highly informative, since the cholinergic system is widespread and involved in many important complex process, and because the system is suppressed under normal conditions. We have found that our genetic animals have enhanced learning, critical period plasticity, heightened anxiety responses, and many more interesting and important phenotypes all awaiting further detailed investigation. The ultimate goal is to understand the cellular basis of behavioral adaptation to allow the individual to better negotiate its complex environment.
The laboratory is seeking scientists with experience in molecular genetics, genetic engineering, in vivo RNA interference, and behavioral pharmacology. We also perform parallel in vitro and in vivo investigations to elucidate the function of these important regulatory molecules, so scientists with a background in tissue culture, stable cell line production, and functional assay development and/or biochemistry would also be a good fit for the lab.
Miwa, JM, Ibanez-Tallon, I, Crabtree, GW, Sanchez, R, Sali, A, Role, LW and Heintz, N (1999) lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 23, 105-114. PMCID:10402197. Cover and previewed manuscript
Ibanez-Tallon, I, Miwa, JM, Wang, HL, Adams, NC, Crabtree, GW, Sine, SM, and Heintz, N (2002) Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron 33, 893-903. PMID:11906696
Ibanez-Tallon, I, Wen, H, Miwa, JM, Xing, J, Tekinay, AB, Ono, F, Brehm, P, and Heintz, N (2004) Tethering Naturally Occurring Peptide Toxins for Cell-Autonomous Modulation of Ion Channel and Receptors in vivo. Neuron 41, 305-311. PMID:15294139.
Miwa, JM, Stevens, TR, King, SL, Calderone, BJ, Ibanez-Tallon, I, Xiao, C, Maki Fitzsimonds, R, Pavlides, C, Lester, HA, Picciotto, MR and Heintz, N (2006) The Prototoxin lynx1 acts on Nicotinic Acetylcholine Receptors to Balance Neuronal Activity and Survival in vivo. Neuron 51, 587-600. PMID:16950157.
Tekinay, AB, Nong, Y, Miwa, JM, Lieberam, I, Ibanez-Tallon, I, Greengard, P, and Heintz, N. (2009) A role for LYNX2 in anxiety-related behavior. Proc. Natl. Acad. Sci. 106, 4477-4482. PMID:19246390. 2 citations. Click here for supplemental.
Miwa, JM, Lester, HA, and Walz, A (2012) Optimizing cholinergic tone through lynx modulators of nicotinic receptors: implications for plasticity and nicotine addiction. Commissioned review, Physiology (Bethesda) 27, 187-99. PMID:22875450
Kobayashi, A, Parker, RL, Wright, AP, Brahem, H, Ku, P, Oliver, KM, Walz, A, Lester, HA, and Miwa, JM (2014) lynx1 Supports Neuronal Health in the Mouse Dorsal Striatum During Aging: an Ultrastructural Investigation. J. Mol. Neurosci. 53, 525-36 PMID:25027556, doi: 10.1007/s12031-014-0352
Nichols, WA, Henderson, BJ, Yu, CY, Parker, RL, Richards, CL, Lester, HA, and Miwa, JM (2014) Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J. Biol. Chem. 289(45), 31423-32, PMID:25193667, pii: jbc.M114.573667
Drenan, RM, Grady, SR, Whiteaker, P, McClure-Begley, T, McKinney, S+, Miwa, JM, Bupp, S+, Heintz, N, McIntosh, JM, Bencherif, M, Marks, MJ, and Lester, HA. (2008) In vivo activation of midbrain dopamine neurons via sensitized, high-affinity α6 nicotinic acetylcholine receptors. Neuron 60, 123-136. PMID:18940593.
Lester, HA, Xiao, C, Srinivasan, R, Son, CD, Miwa, JM, Pantoja, R, Banghart, MR, Dougherty, DA, Goate, AM, and Wang, JC. (2009) Nicotine is a Selective Pharmacological Chaperone of Acetylcholine Receptor Number and Stoichiometry. Implications for Drug Discovery. AAPS, 11, 167-177. PMID:19280351
Drenan, RM, Grady, SR, Steele, AD, McKinney, S+, Patzlaff, NE, McIntosh, JM, Marks, MJ, Miwa, JM, and Lester, HA (2010) Cholinergic Modulation of Locomotion and Striatal Dopamine Release is Mediated by α6α4* Nicotinic Acetylcholine Receptors, J. Neurosci., 30, 9877-9889. PMID:20660270
Srinivasan,R, Pantoja, R, Moss, FJ, Mackey, EDW+, Son, CD, Miwa, JM, and Lester, HA (2010) Nicotine-induced α4β2 nicotinic receptor upregulation: Stoichiometry, β-subunit trafficking motifs, subcellular compartments and endoplasmic reticulum exit sites. J. Gen. Phys. 137, 59-79. PMID: 21187334. Cover manuscript
Richards, CI, Srinivasan, R, Xiao, C, Mackey, EDW+, Miwa, JM, and Lester, HA (2011) Trafficking of α4* nicotinic receptors revealed by superecliptic phluorin: effects of a β4 ALS-associated mutation and chronic exposure to nicotine. J. Biol. Chem. 286, 31241-9. PMID: 21768117
Srinivasan, R, Richards, CI, Mackey, EDW+, Rhee, DS+, Desphande, P, Miwa, JM and Lester, HA (2012) Nicotine remodels the endoplasmic reticulum through the Atf dependent pathway. Mol. Pharmacol. 81, 759-69. PMID: 22379121
Xiao, C, Miwa, JM, Wang, Y, Deshpande, P, and Lester, HA (2015) Nicotinic receptor subtype-selective circuit patterns in the subthalamic nucleus. J. Neurosci., 35(9), 3734-3746, PMID:25740504 *Featured in “This Week in the Journal” at the Journal of Neuroscience, Theresa Esch.
Teja Pammi (work study)
Cecilia Yu Wang
email Ms. Anderson
email Ms. Cummings
email Ms. Dalzon
Huaixing Wang, Ph.D.
email Dr. Wang
email Ms. Lutz
Former Lab Members
Katherine M. Oliver
Yow-Tyng Tim Yeh
Adam Van Handel
Joanna Warran (secondary adviser with Dr. Amber Rice)
Leah Gonzales (work study and BDSI 2014)
Edwin Chan (Mountaintop Project)
Vikram Muller (Summer student researcher from UC Berekely)