Angiotensin-converting enzyme (ACE) has been an important drug target for a long time now – hundreds of millions of people (at the very least) have take ACE1 inhibitors for control of blood pressure, and the coronavirus pandemic brought plenty of new attention to the related ACE2 protein. But here’s a new paper with an illustration of just how many different things are wired together in living systems – ACE has been moonlighting on us.
It’s been known for some time that the ACE protein itself is distributed among many tissues, with some abundances that suggest other functions. Particular brain regions for example, have unusual ACE expression levels, and while those could be related to angiotensin, it’s long been suspected that the enzyme has other substrates in the central nervous system. Studies of various protease inhibitors in the dorsal striatum suggest that there might be some endogenous opioid peptide involved, and now it looks like that one has been identified. It’s MERF, a relative of Met-enkephalin, which is itself a very well known selective endogenous opioid ligand. MERF is the same sequence with an extra Arg-Phe on the end, thus the “RF” in the acronym, from the single-letter amino acid abbreviation. MERF has been studied for some time without really clearing up what its function in the brain is. It was already known that ACE could (in principle) use the MERF peptide as a substrate ,but this new work demonstrates that this is a real effect in the brain.
This work narrows the effect down to the D1 subtype of “medium spiny neurons”, and you can definitely be forgiven if you’ve never heard of them. There are an awful lot of MSNs in brain regions like the striatum and nucleus accumbens, and many of them (but not all) have exclusively the D1 dopamine receptor or the D2 dopamine receptor. (My first project ever on entering the drug industry was on selective D1 antagonists, so I’m always glad to loop back around to that subtype once in a while!) It’s believed that many brain disorders involve (to some degree) imbalanced signaling between these two classes, but doing anything about that has proven difficult. That selective ACE expression in the D1-MSN population, though, suggests at least a handhold for pharmacological intervention.
In this work, the authors show that ACE inhibitors cause increased concentrations of MERF, while other protease inhibitors don’t show the effect. And those ACE inhibitors cause lowering of excitatory synaptic transmission into the D1-MSNs but not into the D2 type. Doing those experiments one by one with various selective ligands showed that it was the mu-opioid receptors that were involved. It’s already known that the D1-MSN circuitry is a big part of the mechanism of addictive drug behavior, so that fits together very well. Further experiments showed that ACE inhibitors themselves did not seem to show any conditioning effects (either rewarding or aversive) in behavioral assays, but what they did do was attenuate the (strong) effects of opioids like fentanyl in such assays. Their hypothesis is that ACE inhibitors increase mu-opioid signaling very locally, in just those D1-MSN neurons, and may well cut down abuse liability by avoiding activation of the mu-opioid pathways in other parts of the brain.
The only real effect of ACE inhibitors on rodent behavior seemed to be increased social interaction, and the paper notes that rodents that show decreased interaction after prolonged social stress also show upregulation of ACE in these brain tissues. Treatment with centrally-acting ACE inhibitors might be beneficial in such cases, and in a number of other CNS disorders – the overall effect is a bit like you would get from a selective reuptake inhibitor for mu-opioid receptors. There has already been a suggestion that such centrally-acting compounds might slow cognitive decline in dementia patients, but to be sure, ACE inhibitors have been associated with other effects (such as reduced autoantibodies in immune disorders).
As someone who has taken lisinopril for years, mostly thinking that I was just affecting my blood pressure, I’m happy to hear about these beneficial effects. Although I’m a bit unnerved (as usual) to see the details of just how many other physiological systems I’m impinging on at the same time. But honestly, every drug is like this. It’s hard to find a receptor or enzyme that does just one thing in one place. Evolution has found all sorts of uses for all sorts of things over the last couple of billion years, and these proteins get repurposed over and over in the usual “whatever works” fashion. That means that there are surely some odd random downsides to ACE inhibition as well, but I think I’ll wait a bit to read up on those. . .
