**5. ACE-2 downregulation**

The SARS-CoV-2 fusion with host cellular membrane occurs at the level of EP pits, structures comprised of the clathrin heavy chains and adaptor protein 2 (AP2), molecules altered by both schizophrenia and the psychotropic drugs [25, 68–70] (**Figure 2**).

The SARS-CoV-2/ACE-2 complexes that are not endocytosed, are shed by ADAM17, contributing to ACE-2 downregulation and increased COVID-19 severity. The exacerbation of SARS-CoV-2 infection is likely the result of virus/ACE-2 complexes dissemination throughout the body via the circulatory system, increasing infectivity (**Figure 3**) [71].

Novel studies have shown that oxidative stress can directly activate ADAM17, triggering ACE-2 downregulation [72, 73]. This takes place as NMDARs interacts with dopamine 1 receptors (D1Rs) activating ADAM17 to excessively cleave ACE-2 from the cell membranes [74–76]. Moreover, ADAM17 can be activated directly by viral proteins NSP6 and ORF9C interaction with sigma-1 receptors [24, 77] (**Table 2**). Furthermore, PS exposure at the cell surface facilitates ACE-2 downregulation, suggesting that the virus may utilize multiple mechanisms to lower this protein and enable infectivity [78].

Another novel study found that ACE-2 contains a calmodulin-binding site, implicating calcium in ADAM17 activation and COVID-19 critical illness [79, 80].

#### **Figure 3.**

*Activation of ANG II-NMDAR axis results in intracellular calcium influx and calmodulin upregulation. Calmodulin-activated ADAM17 orchestrates the shedding of ACE-2/SARS-CoV-2 complexes, leading to ACE-2 downregulation and high infectivity by ACE-2/SARS-CoV-2 circulatory dissemination.*

*COVID-19: A Catalyst for Novel Psychiatric Paradigms - Part 1 DOI: http://dx.doi.org/10.5772/intechopen.96940*

Indeed, it was established that intracellular calcium influx via NMDARs upregulates calmodulin, activating ADAM17 (**Figure 3**) [81, 82]. On the other hand, calmodulin antagonists, including psychotropic drugs amitriptyline, phenothiazines and melatonin, inhibit ACE-2 downregulation and the odds of COVID-19 complications [83]. In addition, recent studies found that SARS-CoV-2 could activate calcium/ calmodulin-dependent protein kinase II (CAMK II), linking the virus further to excitotoxicity (excessive intracellular calcium) [23].

Taken together, ADAM17 promotes ACE-2 downregulation via oxidative stress mediated by NMDARs-upregulated intracellular calcium, mechanisms involved in schizophrenia, drug addictions and COVID-19 critical illness [83–86].
