Halloween is right around the corner, and everyone likes to get spooky! I do fear a lot, in the halloween sense. A trip to “Horror forest” few years back ended with my vocal chords getting maximum exercise! 🙂
It was shown in “Little Albert” that phobias can be conditioned and by conditioning one could trigger the fear response to a stimuli that generally does not induce fear (for example, ringing a bell). While the “Little Albert” experiment is considered as controversial and unethical, today. It does raise the questions Why do we feel fear? What is it that triggers fear in us?
According to these two papers [1, 2], two ion-channel receptors hold the answer to innate and acquired fear. One of the channel receptors is called transient receptor potential channel 5 (TRPC5) . The other one is acid-sensing ion channels (ASICs) .
Acid-sensing ion channel as the name suggests are pH-sensitive and are triggered to open the channel in a low pH environment. They are present in peripheral and central nervous system of mammals. It had been known for many years the relation between ASIC and neurological diseases, such as Huntington’s disease, Multiple Sclerosis, and others. Also, neurotoxins (from snakes, tarantula and others) also affect ASIC’s activation. Recently ASIC has been linked to fear related behaviors. When CO2 levels are increased a threat to life occurs, due to suffocation. In such situations, inhalation of CO2 leads to pH in the brain getting lowered. ASICs present in post-synaptic dendritic regions are activated in low pH and allowing Na+ and to some extent Ca2+ from the extracellular region into the cell, thereby leading membrane depolarization and creates action potentials.
In mice, where ASIC were knocked out, in CO2 rich environments the mice showed reduced response to fear related triggers (these also include forced swim test, tail suspension test).
Apart from H+ activating ASICs there are other ligands, not yet discovered, to activate them as well. In the structure of ASIC, that has a relatively smaller transmembrane region, a 80Å “chalice-like” extracellular domain of the protein protrudes that has numerous cavities and crevices. One of which is the proton-binding site, which not suprisingly is 45Å away from the transmembrane domain. I mean not surprising, since for ASIC to be activated at low-pH the pH “sensor” needs to be placed at the most exposed part of the protein, rather than near the membrane.
This cavity as the authors in  describe is negatively charged and the residues making this cavity are conserved across ASICs. Asp346 and Asp350 are thought of the proton sensing key residues. The authors were surprised to note that this structure lacks a “continuous pore” along the three-fold axis. So, it is highly likely that the protein is able to translate the proton-sensing to open the gate by undergoing domain movement. Specifically, the domain that links the transmembrane region and the proton sensing cavity.
The transient receptor potential channels (TRPC5 and TRPC4) like ASICs are present in various regions of the brain, specifically hippocampus and amygdala. They are voltage-gated channels that are “potentiated by phospholipase C linked receptors”.
TRPC5 knocked mice spent more than twice the amount of time in socially new environments compared to wildtype mice, indicating lower anxiety responses. Also, in elevated plus-maze experiments, the knockout mice spent more time (~20 seconds) in the center, indicating lowered inhibition to open spaces, while the wildtype would generally spend less time (~2 seconds) in the open space.
It is hypothesized that in the absence of TRPC5 the subsequent activation of other receptors such as cholecystokinin2 (CCK2) or others that are glutamate mediated.
For structural information of TRPC5 click here
- Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao GL, Tsvetkov E, Rodig SJ, Van’t Veer A, Meloni EG, Carlezon WA Jr, Bolshakov VY, & Clapham DE (2009). Essential role for TRPC5 in amygdala function and fear-related behavior. Cell, 137 (4), 761-72 PMID: 19450521
- Jasti J, Furukawa H, Gonzales EB, & Gouaux E (2007). Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature, 449 (7160), 316-23 PMID: 17882215
- Wemmie JA, Taugher RJ, & Kreple CJ (2013). Acid-sensing ion channels in pain and disease. Nature reviews. Neuroscience, 14 (7), 461-71 PMID: 23783197