Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects
<p>Organization of the olfactory epithelium and its communication with the olfactory bulb (prepared with <a href="http://Biorender.com" target="_blank">http://Biorender.com</a>).</p> "> Figure 2
<p>(<b>A</b>) Entry of SARS-CoV-2 into the sustentacular cell and the molecular interaction of the virus spike protein and the host cellular receptor ACE2, which depends on spike protein activation by TMPRSS2 and/or furin [<a href="#B46-ijms-25-08527" class="html-bibr">46</a>,<a href="#B49-ijms-25-08527" class="html-bibr">49</a>,<a href="#B53-ijms-25-08527" class="html-bibr">53</a>,<a href="#B59-ijms-25-08527" class="html-bibr">59</a>]. (<b>B</b>) Viral invasion activates Panx1, promoting the release of ATP from the cell [<a href="#B60-ijms-25-08527" class="html-bibr">60</a>]. (<b>C</b>) Extracellular ATP binds to P2 receptors, causing an increase in intracellular Ca<sup>2+</sup> and ROS, which in turn results in DNA damage and cell death. The elevated intracellular Ca<sup>2+</sup> and DNA damage collectively stimulate inflammatory responses, including the synthesis of cytokines like TNF-α and IL-1ß [<a href="#B61-ijms-25-08527" class="html-bibr">61</a>]. (<b>D</b>) Intercellular communication of SC with OSN through gap junctions, creating Ca<sup>2+</sup> waves in the OSN. (<b>E</b>) Increasing intracellular Ca<sup>2+</sup> in OSN activates Ca<sup>2+</sup>-dependent K<sup>+</sup> channels that may mediate a hyperpolarization and subsequently inhibit the odor response or activate Cl<sup>−</sup> channels, reducing the negativity in the cell and causing a depolarization. ACE2, angiotensin-converting enzyme 2 receptor; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CD147, basigin; CNG, cyclic nucleotide-gated channel; IL-1ß, interleukin 1 ß; NRP-1, neuropilin-1; OR, olfactory receptor; OSN, olfactory sensory neuron; PANX1, pannexin 1; P2X4, P2X7, purinergic receptors; ROS, reactive oxygen species; SC, sustentacular cell; TMPRSS 2, transmembrane protease serine type 2; TNF-α, tumor necrosis factor-alpha. This figure was created with <a href="http://Biorender.com" target="_blank">http://Biorender.com</a>.</p> "> Figure 3
<p>TRPV1 participates in anosmia associated with SARS-CoV-2 infection. (1) SARS-CoV-2 infection activates the immune response; (2) inflammatory cells produce proinflammatory cytokines, such as TNF-α, which binds to its receptor (TNF-αR) expressed on the trigeminal ganglion neuron in the OE; (3) TNF-α activates intracellular cascades, including MAPK, p38, and other translational factors, to increase CGRP synthesis and increases the expression and trafficking of TRPV1 to the plasma membrane, thus triggering CGRP release. (4) CGRP binds to its receptor (CGRPR) expressed on OSN. (5) CGRPR activates adenylyl cyclase, which in turn converts ATP to cAMP; (6) cAMP activates a CNG channel, allowing Ca<sup>2+</sup> influx; and (7) Ca<sup>2+</sup> activates a Ca<sup>2+</sup>-dependent K<sup>+</sup> channel (K<sub>Ca</sub>), leading to (8) hyperpolarization and inhibition of odor detection. TGN: trigeminal neuron. AC: adenylyl cyclase; CGRP: calcitonin-related gene peptide; CNG: cyclic nucleotide gated channel; TRPV: transient receptor potential vanilloid; TNFR: TNF-α receptor. TGN: trigeminal nerve ending; OSN: olfactory sensory neuron.</p> ">
Abstract
:1. Introduction
2. Hypotheses Explaining Anosmia
3. The Organization of the Olfactory Epithelium
4. ACE2 and TMPRSS2 Are the Main Entry Receptors for SARS-CoV-2
5. Neuropilin (NRP1) and Basigin (CD147) Are Potential Receptors for Virus Entry
6. Odorant Olfactory Receptors Downregulation May Contribute to Olfactory Dysfunction
7. Transient Receptor Potential Vanilloid (TRPV1) Trafficking May Lead to Odor Inhibition
8. Purinergic Receptors Involvement in Olfactory Signaling (P2X and P2Y Receptors)
9. Interferon Gamma and Interleukins Receptors in Sustentacular Cells
10. Role of Epithelial Sodium Channel (ENaC) in COVID-19 Induced Anosmia
11. Physiological Role of Oscillatory Calcium Transients in Sustentacular Cells and Signal Transduction through Olfactory Sensory Neurons
12. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Al-Saigh, N.N.; Harb, A.A.; Abdalla, S. Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects. Int. J. Mol. Sci. 2024, 25, 8527. https://doi.org/10.3390/ijms25158527
Al-Saigh NN, Harb AA, Abdalla S. Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects. International Journal of Molecular Sciences. 2024; 25(15):8527. https://doi.org/10.3390/ijms25158527
Chicago/Turabian StyleAl-Saigh, Noor N., Amani A. Harb, and Shtaywy Abdalla. 2024. "Receptors Involved in COVID-19-Related Anosmia: An Update on the Pathophysiology and the Mechanistic Aspects" International Journal of Molecular Sciences 25, no. 15: 8527. https://doi.org/10.3390/ijms25158527