Current Research Interest/Projects: Ion Channels As Drug Targets And Their Role In Disease.

There are two primary research goals of this lab. The first is to evaluate the effects of chemicals on ligand and voltage operated ion channels. Currently, we are focusing on the effects of novel peptides on the ligand gated superfamily of ion channels. A second goal is to explore the role of ion channels in genetically mediated disease conditions. In order to achieve these goals, we apply conventional microelectrode, as well as patch clamp, techniques to cells freshly isolated from animals of different ages and genetic make up. Various microscopic techniques are utilized to explore the role of ion channel properties on the development, maintenance, and regeneration of synapses.

Current Project: Nicotinic receptor subunits and synapse development. The goal of this project is to test the hypothesis that spatial heterogeneity of immature (gamma) and mature (epsilon) acetylcholine receptors (AchRs) during the critical phase of neuromuscular junction maturation contributes to heterogeneous end-plate activity. Because of its permeability to calcium, activation of the epsilon AchR will locally increase the intracellular concentration of calcium. Since calcium is both an essential second messenger and a toxic substance, it is logical to suggest that the epsilon form of the AchR evolved to allow highly localized calcium influx which regulates nearby proteins determining neuromuscular junction architecture. To test this hypothesis, combined electrophysiologic and morphologic studies of neonatal and adult wild type as well as epsilon subunit knock out mice are performed. Furthermore, fluorescein Waglerin-1 a peptide selective for the epsilon form of the AchR is used in acute studies to correlate synaptic morphology and function with the distribution of AchR subtypes.

Representative Publications:

Li, X Y & JJ McArdle. Novel transient outward K+ current of mature murine hippocampal neurons. Pflugers Archiv 434:195 202,1997.

Ye, J H & JJ McArdle Waglerin 1 modulates GABA activated current of murine hypothalamic neurons. J. Pharmacol. Exp. Therap. 282:74 80, 1997.

Ye, J H, W H Wu, P Liu & JJ McArdle. Cocaine depresses GABAA current of hippocampal neurons. Brain Research 770:169 175, 1997.

Routh, VH, JJ McArdle & BE Levin. Phosphorylation modulates the activity of the ATP sensitive K+ channel in the ventromedial hypothalamic nucleus. Brain Research 778: 107 119, 1997.

Ye, J H, T Hunt, W H Wu & JJ McArdle. Ondansetron modulates GABAA current of rat central nervous system neurons. European J. Pharmacol. 337: 87 94, 1997

Ye, JH, J Ren, PL Liu & JJ McArdle. Glycine activated currents of neurons freshly isolated from the ventral tegmental area of rats. Brain Research 796:53 62, 1998.

Taylor, P, H Osaka , BE Molles, N Sugiyama , P Marchot, S, Malany, JJ McArdle, SM Sine, & I Tsigelny. Toxins selective for subunit interfaces as probes of nicotinic acetylcholine receptor structure. J. Physiology ( Paris ) 92:79 83, 1998.

Ren, J, J H Ye & JJ McArdle. c AMP Dependent protein kinase modulation of glycine activated chloride current in neurons freshly isolated from rat ventral tegmental area. Brain Research 811:71 78, 1998.

Ye, J H, J Ren & JJ McArdle. Waglerin 1 inhibits of GABAA current of neurons in the nucleus accumbens of neonatal rats. Brain Research 837:29 37, 1999.

McArdle, JJ, T L Lentz, V Witzemann, H Schwarz, SA Weinstein & JJ Schmidt. Waglerin 1 selectively blocks the epsilon form of the muscle nicotinic acetylcholine receptor. J. Pharmacol. Exp. Therap. 289:543 550, 1999.

Ye, J H, J Ren, K Krnjevic, PL Liu & JJ McArdle. Cocaine and lidocaine have additive inhibitory effects on the GABAA current of acutely dissociated hippocampal neurons. Brain Research 821:26 32, 1999.

Ren, J, J H Ye, K Krnjevic, PL Liu & JJ McArdle. Cocaine decreases the glycine induced current in acutely dissociated neurons from rat hippocampus. Eur. J. Pharmacol. 367:125 130, 1999.

Ye, J H, R Schaefer, W H Wu, PL Liu, VK Zbuzek & JJ McArdle. Inhibitory effect of ondansetron on the glycine response of dissociated rat hippocampal neurons. J. Pharmacol. Exp. Therap. 290:104 111, 1999.

Ye, J-H, L Tao, J Ren, R Schaefer, K Krnjevic, PL Liu, DA Schiller & JJ McArdle. 2001. Ethanol potentiation of glycine-induced responses in dissociated neurons of rat ventral tegmental area. J. Pharmacol. Exp. Therap. 296:77-83.

Ye, J-H, L Tao, L Ahu, K Krnjevic & JJ McArdle. 2001. Ethanol inhibition of glycine-activated responses in neurons of ventral tegmental area of neonatal rats. J Neurophysiology 86:2426-2434.

Song, Z, BE Levin, JJ McArdle, N Bakhos & VH Routh. 2001. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 50:2673-2681.

Brenner, H.R., P Flood, JJ McArdle & M Naguib. 2002. Advances in neurobiology of the neuromuscular junction- Implications for the anesthesiologist. Anesthesiology, In Press.

Gladson, BR, R Leonard, E Hayes, J Schafer, JJ McArdle & J Arena. L type calcium channel activity related to glucagon release and its modulation by somatostatin. Submitted.