Bradykinin

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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Bradykinin

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Bradykinin
©2020 PFPC

Recently, numerous studies have hypothesized that dysregulated bradykinin signaling is at the core of COVID-19 (Roche, 2020; Garvin et al., 2020).

The bradykinin B2 receptor forms a complex with angiotensin converting enzyme (ACE), and it is presumed that this plays a role in cross-talk between the renin-angiotensin system (RAS) and the kinin-kallikrein system (KKS).

The B2 receptor is coupled to Gq/11 (Zubakova et al., 2008; Avemary & Diener, 2010). It is dysregulation of the Gq/11-regulated pathways that is at the heart of COVID-19.

COVID-19

Roche JA, Roche R - "A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications" FASEB J 34(6):7265-7269 (2020) doi: 10.1096/fj.202000967. Epub 2020 May 2. PMID: 32359101; PMCID: PMC7267506
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267506/

Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, Mast AE, Justice A, Aronow B, Jacobson D - "A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm" Elife 9:e59177 (2020) doi: 10.7554/eLife.59177. PMID: 32633718; PMCID: PMC7410499
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410499/

Fluoride

"Bradykinin (BK; 0.1 microM) caused Gq/11alpha, but not Gialpha, to rapidly translocate from purified plasma membranes to the supernatant. AlF and GTP also caused translocation of Gq/11alpha immunoreactivity from purified plasma membranes."


(Arthur et al., 1999)

Arthur JM, Collinsworth GP, Gettys TW, Raymond JR - "Agonist-induced translocation of Gq/11alpha immunoreactivity directly from plasma membrane in MDCK cells" Am J Physiol 276(4):F528-34 (1999)
https://pubmed.ncbi.nlm.nih.gov/10198411/

Lückhoff A, Zeh R, Busse R - "Desensitization of the bradykinin-induced rise in intracellular free calcium in cultured endothelial cells" Pflugers Arch 412(6):654-8 (1988) doi: 10.1007/BF00583768. PMID: 3211715
https://pubmed.ncbi.nlm.nih.gov/3211715/

Smith N, Browning CA, Duroudier N, Stewart C, Peel S, Swan C, Hall IP, Sayers I - "Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus" Respir Res 8(1):68 (2007) doi: 10.1186/1465-9921-8-68. PMID: 17903241; PMCID: PMC2117012
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117012/

Gq/11

B1R and B2R couple to G(q/11) and lead via phospholipase C to Ca2+ mobilization (Zubakova et al., 2007).

Arthur JM, Collinsworth GP, Gettys TW, Raymond JR - "Agonist-induced translocation of Gq/11alpha immunoreactivity directly from plasma membrane in MDCK cells" Am J Physiol 276(4):F528-34 (1999)
https://pubmed.ncbi.nlm.nih.gov/10198411/

Zubakova R, Gille A, Faussner A, Hilgenfeldt U - "Ca2+ signalling of kinins in cells expressing rat, mouse and human B1/B2-receptor" Int Immunopharmacol. 8(2):276-8 (2008)
https://pubmed.ncbi.nlm.nih.gov/18182240/

Wilk-Blaszczak MA, Singer WD, Belardetti F - "Three distinct G protein pathways mediate inhibition of neuronal calcium current by bradykinin" J Neurophysiol 76(5):3559-62 (1996) doi: 10.1152/jn.1996.76.5.3559. PMID: 8930294.
https://pubmed.ncbi.nlm.nih.gov/8930294/

Wilk-Blaszczak MA, Gutowski S, Sternweis PC, Belardetti F - "Bradykinin modulates potassium and calcium currents in neuroblastoma hybrid cells via different pertussis toxin-insensitive pathways" Neuron 12(1):109-16 (1994) doi: 10.1016/0896-6273(94)90156-2. PMID: 8292355
https://pubmed.ncbi.nlm.nih.gov/8292355/

Graness A, Adomeit A, Heinze R, Wetzker R, Liebmann C - "A novel mitogenic signaling pathway of bradykinin in the human colon carcinoma cell line SW-480 involves sequential activation of a Gq/11 protein, phosphatidylinositol 3-kinase beta, and protein kinase Cepsilon" J Biol Chem 273(48):32016-22 (1998) doi: 10.1074/jbc.273.48.32016. PMID: 9822674
https://pubmed.ncbi.nlm.nih.gov/9822674/

Fábián G, Szabó CA, Bozó B, Greenwood J, Adamson P, Deli MA, Joó F, Krizbai IA, Szucs M - "Expression of G-protein subtypes in cultured cerebral endothelial cells. Neurochem Int" 33(2):179-85 (1998) doi: 10.1016/s0197-0186(98)00008-4. PMID: 9761462
https://pubmed.ncbi.nlm.nih.gov/9761462/

Smith N, Browning CA, Duroudier N, Stewart C, Peel S, Swan C, Hall IP, Sayers I - "Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus" Respir Res 8(1):68 (2007) doi: 10.1186/1465-9921-8-68. PMID: 17903241; PMCID: PMC2117012
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117012/

Avemary J, Diener M - "Effects of bradykinin B2 receptor stimulation at submucosal ganglia from rat distal colon" Eur J Pharmacol 627(1-3):295-303 (2010) doi: 10.1016/j.ejphar.2009.10.047. Epub 2009 Oct 28. PMID: 19878667
https://pubmed.ncbi.nlm.nih.gov/19878667/

Thyroid

Raspé E, Laurent E, Andry G, Dumont JE - "ATP, bradykinin, TRH and TSH activate the Ca(2+)-phosphatidylinositol cascade of human thyrocytes in primary culture" Mol Cell Endocrinol 81(1-3):175-83 (1991) doi: 10.1016/0303-7207(91)90216-f. PMID: 1665827
https://pubmed.ncbi.nlm.nih.gov/1665827/

Bouhnik J, Savoie F, Baussant T, Michaud A, Alhenc-Gelas F, Corvol P - "Effect of thyroidectomy on rat T-kininogen" Am J Physiol 255(4 Pt 1):E411-5 (1988) doi: 10.1152/ajpendo.1988.255.4.E411. PMID: 3177631
https://pubmed.ncbi.nlm.nih.gov/3177631/
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