Inflammatory pain is often accompanied by a drop in pH (Acidosis). Here investigators hypothesized that modest drops in extracellular pH leading to calcium fluxes acts like a dynamic switch to rapidly mobilize trkA to the cell membrane surface of adult sensory neurons, which in turn serves to increase the sensitivity of these neurons to NGF. The findings reveal a cellular mechanism whereby even small changes in pH can rapidly shift sensitivity to a critical driver of the inflammatory pain state—NGF. They way they demonstrate this shift is quite ingenious: Geoffrey E. Bray, Zhengxin Ying, Landon D. Baillie, Ruiling Zhai, Sean J. Mulligan, and Valerie M.K. Verge. Extracellular pH and Neuronal Depolarization Serve as Dynamic Switches to Rapidly Mobilize trkA to the Membrane of Adult Sensory Neurons. The Journal of Neuroscience, 8 May 2013, 33(19):8202-8215; doi:10.1523/JNEUROSCI.4408-12.2013.
Images: NGF-responsive adult sensory neurons have a large cytoplasmic pool of high-affinity NGF receptors. Six micrometer cryostat sections of L5 DRG processed for high-affinity NGF binding (left) or trkA immunohistochemistry (right) reveal a large cytoplasmic pool of proteins that are able to bind 20 pm radio-iodinated NGF with high affinity or that are immunoreactive to trkA-selective antibodies. Scale bar, 20 μm.
Here're images showing the pH Related switch and rapid migration of TrkA to the membrane
The heightened level of trkA activation likely has ramifications on both short- and long-term sensitization processes as it regulates the activity and expression of a wide variety of receptors, ion channels, and signaling molecules (Mantyh et al., 2011). In the short term, it modulates the activity of receptors and ion channels. For example, NGF decreases the threshold of activation of the nociceptive transient receptor potential vanilloid 1 (TRPV1) receptors (Chuang et al., 2001), mediates TRPV1 trafficking to the membrane (Stein et al., 2006), increases purinergic receptor P2X3-mediated currents and Ca2+ transients (D'Arco et al., 2007) and for sympathetic neurons, rapidly modulates the activity of at least four voltage-gated currents (Luther and Birren, 2009). In the long term, increased NGF can lead to increased transcription of many nociception-associated genes such as its receptors trkA and p75 (Verge et al., 1989, 1992); the neuropeptides Substance P, calcitonin gene-related peptide (Lindsay and Harmar, 1989; Verge et al., 1995), and PACAP; Jongsma Wallin et al., 2001, 2003); sodium channels (Dib-Hajj et al., 1998; Fjell et al., 1999; Kerr et al., 2001); and P2X3 (Ramer et al., 2001; Simonetti et al., 2006). It is also interesting to note that activation of trkA was linked in our study to a parallel activation of p38MAPK, which has been shown to be linked to NGF-mediated increases in ASIC3 expression during inflammation (Mamet et al., 2003).
All Trk Antibodies
Primary Neurons and Astrocytes-Primary human, rat and mouse neurons and astrocytes by Category