‘Busybody’ Protein May Get On Your Nerves, But That’s A Good Thing
Summary: Researchers have identified a protein that is critical for pain signaling.
Source: Salk Institute.
Sensory neurons regulate how we recognize pain, touch, and the movement and position of our own bodies, but the field of neuroscience is just beginning to unravel this circuitry. Now, new research from the Salk Institute shows how a protein called p75 is critical for pain signaling, which could one day have implications for treating neurological disorders as well as trauma such as spinal cord injury.
“The p75 protein is a busybody. It plays a role in many different signaling pathways,” says Salk Professor Kuo-Fen Lee, holder of the Helen McLoraine Chair in Molecular Neurobiology and co-senior author of the new work. “This complexity makes the protein interesting to study. In this latest research, we discovered that, in addition to its other functions, it’s also required for the survival of certain pain-sensing neurons.” The results are published October 17, 2017, in Cell Reports.
Previous research by Lee’s lab had shown that p75 is involved in a signaling pathway that regulates the development of sensory neurons–cells which transmit our sensation of pain, touch and muscle tension–in the dorsal root ganglia.
In this latest study, the investigators collaborated with a team at the University of Michigan led by co-senior author Brian Pierchala to further learn about the role of p75 in the development of sensory neurons. They studied mice lacking p75 only in the sensory neurons. When these mice were born, their sensory neurons were normal. But by the time they were six months old, some of those sensory neurons had degenerated, particularly the populations of cells that usually transmit pain signals.
It turned out that p75 partners with another class of receptors, called the GDNF (glial cell-derived neurotrophic factor) receptor family. The p75 protein binds to one such receptor called Ret, which is associated with some neurological conditions as well as certain types of cancer. Members of the GDNF family support the survival of sensory neurons that transmit the pain signal and p75 enhances this survival-promoting effect by interacting with Ret. When p75 was removed, the survival-promoting signal from GDNF family members was reduced and the sensory neurons that need this signal to survive gradually degenerated.
“In this particular study, one of the remarkable findings is that this relationship between Ret and p75 exists at all. It’s something that wasn’t previously known,” says Zhijiang Chen, a postdoctoral fellow in Lee’s lab and one of the paper’s co-first authors. “This research adds further significance to the role of p75 as a master regulator for many different signaling pathways that are vital for the nervous system to function normally.”
Lee says that although he doesn’t know of any human disorders that are associated with the loss of p75 in particular, pain sensation is obviously vital for quality of life. “We do know of people who have these kinds of sensory deficits, and it can be serious problem,” he says. “Thanks to this research, we now know more about the broad influence of the p75 protein.”
Future studies will look at the role p75 plays in two other types of cells — glial cells and skin cells. The investigators also plan to look in more detail at the role of p75 in different parts of the body.
“We know that in the sacral region, there is a high percentage of sensory neurons with strong p75 expression,” Lee says.
Other authors on the study are Bertha Dominguez, Yoshinobu Harada, Tasha Bengoechea of Salk; Weichun Lin of UT Southwestern Medical School; and Christopher R. Donnelly and Alan S. Halim of the University of Michigan.
Funding: This research was supported by grants from the NIH, the Clayton Foundation, the Schlink Foundation, the Gemcon Family Foundation, and the Joe W. and Dorothy Dorsett Brown Foundation.
The low-affinity nerve growth factor receptor (nerve growth factor receptor (TNFR superfamily, member 16), also called the LNGFR or p75 neurotrophin receptor) is one of the two receptor types for the neurotrophins, a family of protein growth factors that stimulate neuronal cells to survive and differentiate. LNGFR is a member of the tumor necrosis factor receptor (TNF receptor)superfamily – indeed, LNGFR was the first member of this large family of receptors to be characterized.
The neurotrophins are composed of four proteins, all of which bind to the LNGFR: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4).
Nerve growth factor, the prototypical growth factor, is a protein secreted by a neuron’s target. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high-affinity receptor tropomyosin receptor kinase A (TrkA), and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons.
The activation of TrkA by NGF is critical in inducing the survival and differentiation caused by this growth factor.
However, NGF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkA (pronounced “Track A”) and the LNGFR.
Trk family of receptor tyrosine kinases
TrkA is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkB and TrkC. Also, there are other neurotrophic factors structurally related to NGF: BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, TrkB binds and is activated by BDNF, NT-4, and NT-3, and TrkC binds and is activated only by NT-3.
Neurotrophins activating LNGFR may signal a cell to die via apoptosis, but this effect is counteracted by anti-apoptotic signaling by TrkA, TrkB, or TrkC signaling in cells that also express those receptors. LNGFR functions in a complex with Nogo receptor (NgR, Reticulon 4 receptor) to mediate RhoA-dependent inhibition of growth of regenerating axons exposed to inhibitory proteins of CNS myelin, such as Nogo, MAG or OMgP. LNGFR also activates a caspase- dependent signaling pathway that promotes developmental axon pruning, and axon degeneration in neurodegenerative disease.
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