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9.16.2014

Notable Study Promotes Distinct Pannexin Conformations

A study led by Gerhard Dahl, M.D., professor of physiology and biophysics, describes a significant finding that shows different stimuli can induce different conformations of a membrane channel with distinct conductance and permeability. Only one other channel, the P2X7 receptor, has been associated with such a phenomenon.

Published September 10 in the prestigious journal Science Signaling, the study, “The membrane protein Pannexin1 forms two open-channel conformations depending on the mode of activation,” resolves a controversy about the function of Pannexin1 (Panx1) channels. Panx1 has been shown to form a large adenosine triphosphate (ATP) release channel and has an important role in several functions, including the innate immune response, ciliary beat in airway epithelia and oxygen supply in the vascular system.

This view was recently challenged by the association of Panx1 with a small conductance channel with chloride, but no ATP permeability. The new study shows that Panx1 can form both types of channel and that the stimulus determines which channel conformation is assumed. The study findings also were featured in an editorial published in the Journal of General Physiology.

Dahl says understanding Panx1 physiology is important, because the membrane protein is associated with several pathological settings, including neuronal cell death in Crohn’s disease, migraine, status epilepticus and secondary cell death.

In particular, the interaction of the Panx1 channel with potassium ions appears to be a key element of secondary cell death as observed in central nervous system injury and stroke.

To test whether two activation mechanisms – voltage and potassium ions (K+) – produce equivalent channel function, Dahl and his team expressed Panx1 in Xenopus oocytes, a genus of aquatic frog cells that are ideally suited for exogenous expression of proteins.

“Comparing ATP release from the Xenopus oocytes expressing Panx1 and the control (uninjected) oocytes, we observed under control of membrane potential by voltage clamp that ATP release was induced by increasing extracellular K+ and occurred independently of the membrane potential,” Dahl said. “Activation of the channel by depolarization alone, however, did not result in ATP release.”

Next, the team tested its hypothesis that the two permeability states of Panx1 channels correlate with the two conductance states.

The large conductance channel activity was clearly visible by changing the ionic composition of the perfusate from sodium (Na+) to K+ and back again.

“Based on this data, our study shows that Panx1 channels can exhibit distinct and unique conductances and permeabilities in the same cellular environment with only the stimulation modus as the variable,” Dahl said. “Because we observed these two channel properties in the same Panx1 expressing oocytes, but under two different activation conditions, it is unlikely that other proteins modulate Panx1 to assume different conductances and permeabilities as has been previously suggested.”

Dahl says a series of Panx1 inhibitors have already been identified, so the next step is to translate these findings.

In addition to first author Junjie Wang, Ph.D., post-doctoral associate, other Miller School co-authors are Feng Qiu, Ph.D., assistant scientist, and David G. Jackson, graduate student in the Department of Physiology and Biophysics.

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