scholarly journals Function of K2P channels in the mammalian node of Ranvier

2021 ◽  
Author(s):  
Jürgen R. Schwarz
Keyword(s):  
Node Of Ranvier ◽  
K2p Channels

scholarly journals A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

2020 ◽  
pp. 247255522097612
Author(s):  
David McCoull ◽  
Emma Ococks ◽  
Jonathan M. Large ◽  
David C. Tickle ◽  
Alistair Mathie ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Point Of View ◽  
Resting Membrane Potential ◽  
Small Molecule Activation ◽  
Target Class ◽  
Index Set ◽  
Diverse Range ◽  
K2p Channels ◽  
Additional Approach ◽  
Pore Domain

Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a “target class” approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration–response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

scholarly journals The Role of the Ankyrin-Binding Protein NrCAM in Node of Ranvier Formation

2003 ◽  
Vol 23 (31) ◽  
pp. 10032-10039 ◽  
Author(s):  
Andrew W. Custer ◽  
Katia Kazarinova-Noyes ◽  
Takeshi Sakurai ◽  
Xiaorong Xu ◽  
William Simon ◽  
...  
Keyword(s):  
Binding Protein ◽  
Node Of Ranvier

scholarly journals Expression of cytotactin in the normal and regenerating neuromuscular system.

1989 ◽  
Vol 108 (2) ◽  
pp. 625-635 ◽  
Author(s):  
J K Daniloff ◽  
K L Crossin ◽  
M Pinçon-Raymond ◽  
M Murawsky ◽  
F Rieger ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Neuromuscular Junction ◽  
Schwann Cells ◽  
Node Of Ranvier ◽  
Myotendinous Junction ◽  
Neuromuscular System ◽  
Peripheral Nerve Damage ◽  
Neural Cell Adhesion ◽  
Developing Cerebellum

Cytotactin is an extracellular glycoprotein found in a highly specialized distribution during embryonic development. In the brain, it is synthesized by glia, not neurons. It is involved in neuron-glia adhesion in vitro and affects neuronal migration in the developing cerebellum. In an attempt to extend these observations to the peripheral nervous system, we have examined the distribution and localization of cytotactin in different parts of the normal and regenerating neuromuscular system. In the normal neuromuscular system, cytotactin accumulated at critical sites of cell-cell interactions, specifically at the neuromuscular junction and the myotendinous junction, as well at the node of Ranvier (Rieger, F., J. K. Daniloff, M. Pinçon-Raymond, K. L. Crossin, M. Grumet, and G. M. Edelman. 1986. J. Cell Biol. 103:379-391). At the neuromuscular junction, cytotactin was located in terminal nonmyelinating Schwann cells. Cytotactin was also detected near the insertion points of the muscle fibers to tendinous structures in both the proximal and distal endomysial regions of the myotendinous junctions. This was in striking contrast to staining for the neural cell adhesion molecule, N-CAM, which was accumulated near the extreme ends of the muscle fiber. Peripheral nerve damage resulted in modulation of expression of cytotactin in both nerve and muscle, particularly among the interacting tissues during regeneration and reinnervation. In denervated muscle, cytotactin accumulated in interstitial spaces and near the previous synaptic sites. Cytotactin levels were elevated and remained high along the endoneurial tubes and in the perineurium as long as muscle remained denervated. Reinnervation led to a return to normal levels of cytotactin both in inner surfaces of the nerve fascicles and in the perineurium. In dorsal root ganglia, the processes surrounding ganglionic neurons became intensely stained by anticytotactin antibodies after the nerve was cut, and returned to normal by 30 d after injury. These data suggest that local signals between neurons, glia, and supporting cells may regulate cytotactin expression in the neuromuscular system in a fashion coordinate with other cell adhesion molecules. Moreover, innervation may regulate the relative amount and distribution of cytotactin both in muscle and in Schwann cells.

Ultracytochemical localization of membrane-bound enzymes in the node of Ranvier

1989 ◽  
Vol 20 (3-4) ◽  
pp. 207-215
Author(s):  
Kenichirou Inomata ◽  
Fumio Nasu ◽  
Kazuhiro Tomiyasu
Keyword(s):  
Node Of Ranvier ◽  
Membrane Bound ◽  
Membrane Bound Enzymes
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