Peripheral neurons, CRH, and sickness behavior

[ScoutB]

That Familial Episodic Pain Syndrome paper (apparently I only remember the most recent paper I've read) had an interesting example of how the ion channel works differently in different species:

A fascinating aspect of TRPA1 activation lies in interspecies discrepancies. Some electrophilic thioaminal-containing compounds are able to activate rat TRPA1 while others inhibit human TRPA1 (Chen et al., 2008). This difference is due to key amino acids situated in the S6 segment. A similar story applies to caffeine, which was shown to activate mouse TRPA1 but to inhibit the human channel (Nagatomo and Kubo, 2008), and menthol, which activates mammalian TRPA1, blocks nonmammalian TRPA1 (Xiao et al., 2008), and exerts a bimodal action on murine TRPA1 (Karashima et al., 2009). Therefore, similar compounds are able to exert opposite effects in different species and this suggests a complex gating mechanism for TRPA1 in which amino acid substitutions at key positions determine agonist binding and gating.

It reminded me of how human biology likes to reuse the same molecules in different tissues in different, and sometimes opposing, ways. And made me think that maybe this is not just convenience, but also because that molecule has "strong relationships" with other molecules in the relevant system (meaning high binding affinities or something, idk, I'm over my head), and then it only takes a tweak somewhere else to swap the actual direction of its effect. (?)

So all that to say, I wonder if it makes sense to view CRH's interactions with immune things in mice as clues that CRH might interact with similar parts of the human immune system, but that the exact problem it solves and actual direction of some of its effects in humans could be different or even opposite? This idea would probably be more useful if we knew exactly *how* CRH was mediating the sickness behaviour in mice.

Basically, I guess it seems like the answer to the below question could be "yes, involved, but possibly in a different way." ?

So I guess it comes down to whether CRH is involved in regular human "sickness behavior" or not.

I wonder if we know anything about CRH in primates..

 

[jnmaciuch]

That Familial Episodic Pain Syndrome paper (apparently I only remember the most recent paper I've read) had an interesting example of how the ion channel works differently in different species:


It reminded me of how human biology likes to reuse the same molecules in different tissues in different, and sometimes opposing, ways. And made me think that maybe this is not just convenience, but also because that molecule has "strong relationships" with other molecules in the relevant system (meaning high binding affinities or something, idk, I'm over my head), and then it only takes a tweak somewhere else to swap the actual direction of its effect. (?)

So all that to say, I wonder if it makes sense to view CRH's interactions with immune things in mice as clues that CRH might interact with similar parts of the human immune system, but that the exact problem it solves and actual direction of some of its effects in humans could be different or even opposite? This idea would probably be more useful if we knew exactly *how* CRH was mediating the sickness behaviour in mice.

Basically, I guess it seems like the answer to the below question could be "yes, involved, but possibly in a different way." ?


I wonder if we know anything about CRH in primates..

Could be! Though in the case of CRH, my instinct is that it’s more likely to be evolutionarily conserved. TRPA1 is one of many different chemosensitive proteins, where all the proteins that class have varied structures specifically so they can be attuned to different stimuli. There’s a lot of wiggle room for things to mutate without inducing a fitness cost for the animal.

In contrast, CRH is a pretty central linchpin in a lot of fundamental homeostatic processes. And in the case of its potential connection to sickness behavior, it would be a linchpin for a mechanism that spans multiple parts of the body, neural circuits, etc. Those types of fundamental multisystem processes tend to be conserved across species because small mutations are way more likely to throw a wrench in the whole system. Though it may have just happened to work out differently between human and mouse for reasons I couldn’t account for!