Eugene M. Silinsky, PhD Professor and Chair Molecular Pharmacology and Biological Chemistry Presynaptic and postsynaptic mechanisms underlying fast neurotransmission and modulation Curricula: Neurobiology Pharmacology and Toxicology       Structural Biology and Biochemistry E-mail:   e-silinsky@northwestern.edu

Nerve endings communicate with their receiving cells at synaptic junctions by the secretion of primary neurotransmitter substances and the co-release of neuromodulatory substances. The main interests of my laboratory are the mechanisms underlying the secretion and effects of neurotransmitter substances with current emphasis on the processes by which co-released adenosine derivatives modulate or mediate excitatory synaptic transmission.

With respect to presynaptic events, We have shown that skeletal neuromuscular depression is due to the neural release of ATP, which, after degradation to adenosine, acts to inhibit the subsequent release of the neurotransmitter acetylcholine (ACh). The clinical implications of these results are intriguing. Specifically, could specific adenosine receptor antagonists maintain a high safety factor at the neuromuscular junction and thus alleviate the symptom of patients in disease states where skeletal muscle is readily fatigued (e.g. myasthenia gravis)? We are examining what strategic parts of the secretory apparatus are the targets for adenosine by using, botulinum toxins, knockout mice and antibodies delivered in liposomes as tools in conjunction with electrophysiological techniques.

With respect to postjunctional events, we employed patch clamp techniques to be among the first to demonstrate that ATP mediates fast synaptic excitation between adult mammalian neurons. These studies also demonstrated a remarkable interaction between P2X ATP receptors and nicotinic receptors for ACh; activation of these two types of apparently independent channels are mutually occlusive. We will be studying these interactions further in adult neurons and in cloned human nicotinic and P2X ATP receptors expressed in tandem.

Publications:

Hirsh, J.K., Searl, T.J and Silinsky, E.M. Regulation by Rab3A of an endogenous modulator of neurotransmitter release at mouse motor nerve endings. The Journal of Physiology 545.2, 337-343, 2002.

Silinsky, E.M. and Searl, T,J. Phorbol esters and neurotransmitter releease: more than just protein kinase C British Journal of Pharmacology, 138, 1191-1201, 2003.

Hirsh, J.K. and Silinsky, E.M. (2002). Inhibition of spontaneous acetylcholine secretion by 2-chloroadenosine as revealed by a protein kinase inhibitor at the mouse neuromuscular junction British Journal of Pharmacology, 130, 418-424, 2002.

Searl, T.J and Silinsky, E.M. Evidence for two distinct processes in the final stages of neurotransmitter release as detected by binomial analyses in calcium and strontium solutions.  The Journal of Physiology 593.3 693-705,2002

Silinsky, E.M., Searl, T.J, Redman, R.S. and Hirsh, J.K. Release and effects of ATP and its derivatives at cholinergic synapses. Drug Discovery Research, 52, 22-33, 2001

Silinsky, E.M. Antagonism of calcium currents and neurotransmitter release by barium ions at frog motor nerve endings British Journal of Pharmacology, 129, 360-366, 2000.

Searl, T.J & Silinsky, E.M. The phosphatidylinositol-4-kinase inhibitor phenylarsine oxide blocks evoked neurotransmitter release by reducing calcium entry through N-type calcium channels. British Journal of Pharmacology, 130, 418-424, 2000.

Silinsky, E.M., Hirsh, J.K., Redman, R.S. & Watanable, M. Quantal ATP release from motor nerve endings and its role in neuromuscular depression. Progress in Brain Research, 120, 145-158, 1999.

Searl, T.J. & Silinsky, E.M. Crosstalk between apparently independent receptors. Journal of Physiology, 513.3, 629, 1998.