Stephen Smith Laboratory

OHSU Clinic: Stephen Smith Laboratory

Clinic Description

Underscoring the importance of synaptic transmission are the observations that changes in interneuronal communication underlie changes in behavior, and that derangements in synaptic transmission manifest as neurological diseases. The small nerve terminals found at the vast majority of synapses in the mammalian nervous system have been difficult to study directly because of their tiny size and inaccessibility. We are interested in the mechanisms by which ion channels regulate synaptic transmission and have devised a method to record directly from single small nerve terminals. We are using this approach to study the properties of ion channels in small nerve terminals and how they are modulated by changes in the extracellular microenvironment.

The long-term goal of the Smith laboratory is to understand how presynaptic ion channels regulate neurotransmission in the brain under physiological conditions. These projects involve the use of electrophysiological and optical techniques to study a variety of voltage- and transmitter-modulated channels. Our interests include the role of [Ca2+] as a critical signal at the synapse. Much more is known about signaling downstream of changes in intracellular [Ca2+] than about the impact of changes in extracellular [Ca2+] ([Ca2+]o). Yet [Ca2+]o is likely to undergo significant changes as a result of electrical activity. Our hypothesis is that a decrease in synaptic cleft [Ca2+] is an important signal that may regulate synaptic efficacy. By patch clamping single, neocortical nerve terminals, we have recently discovered a novel, Ca2+-based signaling pathway comprised of a voltage-sensitive non-selective cation (NSC) channel that is activated by decreases in [Ca2+]o. This interesting finding poses a number of questions: what is the mechanism by which changes in [Ca2+]o are detected and transduced to alterations in membrane conductance? Is the Ca2+ sensor-NSC channel signaling pathway modulated by other agents at the nerve terminal? What is the physiological impact of the Ca2+ sensor-NSC channel signaling pathway on synaptic transmission? We are currently addressing these questions by combining molecular and electrophysiological techniques. The picture shows a current trace (red) recorded from a nerve terminal following a depolarization. A smooth outward current is activated at low extracellular [Ca2+] and surmounted by single channel potassium currents. The traces are located within an electronmicrograph of an isolated neocortical nerve terminal (EM by Dr N.C. Harata). These nerve terminals have intact vesicle turnover and can be used to study ion channel function and regulation at small nerve terminals.

Another area of interest in the lab addresses the hypothesis that intracellular contents that leak from damaged cells may have important actions on ion channel function in adjacent neurons. We have begun to study the actions of some of these molecules on ion channels found in neurons using whole-cell patch clamp recording techniques. Polyamines are one such group of compounds that are released at times of brain injury and also have neuroprotective actions. We have demonstrated that polyamines, modulate voltage-activated calcium channels and that this modulation is highly pH-dependent. Since extracellular pH changes at times of brain injury, we are investigating whether the modulation of voltage-activated calcium channels may explain the neuroprotective action of polyamines.

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OHSU Campus, BRB 340A
3181 SW Sam Jackson Park Road
Portland,  OR  97239

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