Signalling in Pain

How are ion channels regulated in pain sensing neurons?

Accessory proteins

Acid-sensing ion channels are know to bind to a whole host of molecules including PICK1, PSD-95, Lin7b, and many others. An interesting family of proteins that bind to and regulate ASICs are the Stomatin family of integral membrane proteins (Stomatin, Stomatin-like proteins 1-3). These proteins regulate ASIC channels in an isoform specific manner, largely reducing the total ASIC current. The mechanism of this reduction in current is an open question and one that we are interested in tackling.

 

How do the properties of ion channels change during inflammatory pain?

In response to injury, damaged tissue undergoes a complex immune reaction called inflammation. In addition to aiding in recovery, the extracellular signals associated with inflammation alter the electrical properties of nociceptive nerve terminals by directly exciting the nerve terminals (ATP, protons, 5-HT) or by sensitizing the nerve (bradykinin, prostaglandins, cytokines) through activation of membrane receptors. The mechanisms of nerve sensitization are thought to involve indirect effects on ion channels at the nerve terminals through activation of membrane receptors.

One emerging mechanism involves changes in the lipid composition of the plasma membrane through activation of membrane receptors that bind to inflammatory mediators like bradykinin or nerve growth factor. Both phosphoinositides in the membrane as well as lipid signaling molecules like diacylglycerol and arachidonic acid have been shown to alter ion channel function. The synthesis and degradation of these lipid molecules can be controlled by activation of membrane receptors. Although cell surface receptor-stimulated lipid signaling is of broad significance to biology, the molecular mechanisms by which it occurs are poorly understood.

PIPmethodscurrents

I use fluorescent biosensors and controllable phosphatases that can both monitor and alter the phosphoinositide composition of the plasma membrane. In combination with electrophysiological recordings, these tools allow me to determine the dynamics of phosphoinositide regulation in neurons as well as determine how changing phosphoinositide levels alters the properties of ion channels. On example is the voltage-sensitive phosphatase (VSP), which degrades PI(4,5)P2 in response to membrane depolarization, allows for the examination of the effect of PI(4,5)P2 on ion channel function. Above you can see that activation of the phosphatase reduces the plasma membrane level of PI(4,5)P2 which  reduces the acid-sensitive ion channel current.