“Ouch!” Thanks to our always-alert sensory neurons that provide a spatial sense of self (proprioception) and pain (nociception), we receive an early warning to any noxious stimuli (think needle prick or a hot stove). Sometimes our responses to these stimuli are exaggerated and we experience hypersensitivity to pain. Remember how painful lukewarm water feels on sunburnt skin? This hyperalgesia can be very severe. Examples include the intense neuropathic pain caused by blowing on the skin of patients with nerve damage, the muscular pain associated with the disabling pain disorder fibromyalgia, and the excruciatingly painful phantom limb syndrome.
So what turns a warning bell into a death knell?
Previous work has implicated the hypersensitive response to pain to the hyperexcitability of sodium-activated potassium (KNa) channels abundantly expressed in the dorsal root ganglion (DRG). The DRG mainly consists of cell bodies of sensory neurons at the dorsal root of the spine, where they relay sensory information to the central nervous system (Kaczmarek, 2013). One such KNa channel called Slack plays a pivotal role in regulating action potentials by “resetting” the membrane potential (repolarization). The function of Slack channels is to determine the length of the excitation event (depolarization), and therefore the length of action potentials. In many neuronal cell types, when the Slack channels are less activated, they become hyperexcitable, but this mechanism has not been well studied in DRG neurons. A recent study in The Journal of Neuroscience explored the contribution of KNa current in DRG neurons and its relation to pain hypersensitivity.
The team of Nuwer et al. used DRG neuronal cultures expressing the Slack channel to perform whole-cell patch clamp electrophysiology. They were able to reduce the Slack channel current by as much as 50% by activating a cellular signaling pathway (Protein Kinase A or PKA), to which Slack is responsive. It is known that inhibiting potassium current increases neuronal excitability, but how does activating PKA inhibit the “Slack component” (KNa) of potassium current?
One possibility is that the amount of Slack in the membrane was reduced due to changes in protein trafficking. To test this hypothesis, the research team used live-imaging microscopy to visualize and quantify the amount of fluorescence-tagged Slack at the neuronal membrane. The fluorescence-tagged Slack allowed the researchers to observe the amount of Slack channels that are inserted or removed from the neuron’s membrane. Indeed, PKA did change protein trafficking! Their results showed that PKA-activation decreased the amount of Slack in the cell membrane suggesting a PKA-induced internalization of the channel. The distribution of Slack in the membrane of neurons in the dorsal root ganglia helps contribute to the normal (non-hyperexcitable) state of the neurons. This study marks the first ever conclusive demonstration of the direct involvement of Slack in DRG neuronal hyperexcitability!
The results of this study are exciting because they have identified a new molecular pathway that regulates the excitability of sensory neurons in the spinal cord! With this information, future drugs may be developed that could control pain hypersensitivity by regulating this pathway. In the meantime, let’s remember to be thankful to our Slack channels for never slacking off!
Written by Sushmitha Gururaj.
Kaczmarek L.K. (2013). Slack, Slick, and Sodium-Activated Potassium Channels, ISRN Neuroscience, 2013 1-14. DOI: 10.1155/2013/354262
Nuwer M.O., Picchione K.E. & Bhattacharjee A. (2010). PKA-Induced Internalization of Slack KNa Channels Produces Dorsal Root Ganglion Neuron Hyperexcitability, Journal of Neuroscience, 30 (42) 14165-14172. DOI: 10.1523/JNEUROSCI.3150-10.2010
Nuwer M.O., Picchione K.E. & Bhattacharjee A. (2009). cAMP-dependent kinase does not modulate the Slack sodium-activated potassium channel, Neuropharmacology, 57 (3) 219-226. DOI:10.1016/j.neuropharm.2009.06.006
Images made by Anita Ramanathan and Ryan Jones.
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