July 08, 2020

TREK-1 and TRAAK are principal K+ channels at the Nodes of Ranvier for rapid action potential conduction on mammalian myelinated afferent nerves

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Jianguo Gu 14 croprJianguo Gu, Ph.D., Edward A. Ernst Endowed Chair and professor in the Department of Anesthesiology and Perioperative Medicine, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members.

His study, “TREK-1 and TRAAK are principal K+ channels at the Nodes of Ranvier for rapid action potential conduction on mammalian myelinated afferent nerves,” was recently published in the Cell Press journal Neuron. Gu, his postdoctoral fellow Hirosato Kanda, Ph.D., and other colleagues at UAB reported that two ion channels—TREK-1 and TRAAK—act as the principal potassium channels in the Nodes of Ranvier of myelinated nerves in mammals.

Since 1939, the Nodes of Ranvier have been known to act like relay stations placed about 1 millimeter apart along the myelinated nerve to conduct mammalian nerve impulses at rates of 50 to 200 meters per second. Gu’s team found that the TREK-1 and TRAAK channels at the Nodes of Ranvier were required for high-speed and high-frequency saltatory, or “hopping” conduction along myelinated afferent nerves. In their study, knockdown of the channels reduced nerve conduction speed by 50 percent, and behavioral experiments showed that knockdown in the nerve reduced an animal model’s aversive reaction to a flick of its whisker. Additionally, the two leak potassium channels allowed very rapid repolarization of action potentials at the Nodes of Ranvier, with high frequency and rapid conductance of the myelinated rat nerves. Interestingly, the TREK-1 and TRAAK channels appeared to form heterodimers in the Nodes of Ranvier.

These new fundamental findings have implications in neurological diseases or conditions where nodal dysfunctions affect action potential conduction, which includes carpal tunnel syndrome, Guillain-Barré syndrome, multiple sclerosis, spinal cord injuries, and amyotrophic lateral sclerosis.

This knowledge is crucial to understanding and developing new neurological disease treatments and cultivating new therapies. Read more about Dr. Gu's study from UAB News here.

The School of Medicine communications staff sat down with Dr. Gu to gain insights about his research, UAB, and the science community.

Q: What compelled you to pursue this research?

Rapid conduction of nerve impulses are critical in life and rely on action potential leaps through the Nodes of Ranvier (NRs) along myelinated nerves. While NRs are the only sites where action potentials can be regenerated during nerve conduction on myelinated nerves, ion channel mechanisms underlying the regeneration and conduction of action potentials at mammalian NRs remain incompletely understood because of technical challenges in making electrophysiological recordings at NRs. We developed an in situ pressure-patch-clamp recording technique, and for the first time directly made patch-clamp recordings at intact NRs. This allowed us to pursue this research and discovered a new ion channel mechanism of action potential regeneration and rapid conduction along myelinated nerves of mammals.

Q: What was your most unexpected finding?

The most unexpected finding in this study is that TREK-1 and TRAAK channels, the thermosensitive and mechanosensitive two-pore domain potassium channels (K2P), provide a molecular mechanism responsible for rapid nerve conduction in mammals. This challenges conventional model of action potential regeneration and conduction along nerve fibers. In this study, we show that TREK-1 and TRAAK are specifically clustered at nodes of Ranvier with density 3000-fold higher than that at other parts of nerves. Furthermore, we demonstrate for the first time that these K2P channels, but not voltage-gated K+ channels as in other parts of nerves, are required for rapid action potential repolarization at Nodes of Ranvier. More importantly, these K2P channels permit high-speed and high-frequency nerve impulse conduction along myelinated nerves and are essential for prompt sensory behavioral responses in vivo.

Q: How do you feel your research will impact the science community?

We believe that the use of TREK-1 and TRAAK channels for rapid AP conduction represents an evolutionary advancement to permit high-frequency and high-speed action potential conduction on myelinated nerve of mammals. It is conceivable that this advancement may be widely adopted in mammalian nervous systems including other rapidly conducting somatosensory afferent nerves, specialized sensory nerves such as optical and auditory nerves, motor nerves, and ascending and descending projection nerves in the central nervous system. Therefore, we believe that our research will have a very broad impact in the neuroscience community.

Q: What is your research’s relevance to human disease?

Action potential conduction on myelinated nerves is known to be impaired in many human diseases such as carpal tunnel syndrome, multiple sclerosis, spinal cord and brain injuries, amyotrophic lateral sclerosis, diabetic neuropathy, degeneration of optical and auditory nerves, Guillain-Barré syndrome, and other inflammatory demyelinating neuropathy. This leads to motor disorders such as muscle weakness and paralysis as well as sensory dysfunctions such as loss of touch, vision, and hearing. Indeed, we have shown that the loss of function of TREK-1 and TRAAK channels at NRs in our animals impairs in vivo sensory behavioral responses. This raises the possibility that the loss of function of TREK-1 and TRAAK channels at Nodes of Ranvier may also occur in human diseases to contribute to the impairment of sensory and motor functions. Therefore, our findings may have broad pathological and therapeutic implications for human neurological diseases.

Q: When did you know you had an important discovery?

We realized that we had an important discovery when we recorded unexpectedly large amounts of K+ currents mediated by TREK-1 and TRAAK channels at NRs because this indicated an unconventional nature of axonal membranes at NRs of myelinated nerves in mammals. However, it took us years to confirm the physiological significance and to realize the pathological implications of this study. Our findings in this study may be translated into new therapeutic strategies for treating human neurological diseases associated with the impaired action potential conduction along myelinated nerves.

Read the publication here.