On 2015 Nov 28, Friedrich Thinnes commented:

Arguments for plasmalemmal VDAC-1 to form the channel part of VRAC

The inclusion of VDAC-1 = voltage dependent anion channel of isotype-1 into the plasma membrane of mammalian cells was first demonstrated in 1989, this by its immuno-topochemical flagging on human B lymphocyte, and those data were meanwhile corroborated by several laboratories using manifold approaches world wide (1-4).

Concerning the function of plasmalemmal VDAC-1 (5-9) it has been shown that the channel is involved in cell volume regulation. Cell outside applied monoclonal mouse anti-human type-1 porin antibodies blocked the RVD of HeLa cells, proving that VDAC-1 is involved in the process. HeLa cells pre-incubated with the antibodies dramatically increased their volume within about 1 min after a stimulus by hypotonic Ringer solution, but did not move backward towards their starting volume, thus indicating abolished RVD.

To notice, corresponding blocking effects were induced by the established anion channel inhibitor DIDS or BH4BClXL peptides, respectively. Video camera monitoring of cell size over time was used in this direct and noninvasive approach (9; www.futhin.de Supplement 1). Corroboration of these data came from the laboratory of Dr. R. Boucher (10) using VDAC knock out mice, this study, furthermore, pointing to the channel as an ATP pathway.

First data concerning the involvement of plasmalemmal VDAC-1 in the apoptotic process came from Dr. F. Elinder´s laboratory, demonstrating that opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli (11). In line, the laboratory of Dr. Raquel Marin demonstrated that voltage dependent anion channel (VDAC-1) participates in amyloid Aß-induced toxicity and also interacts with the plasma membrane estrogen receptor alpha (mERa) in septal and hippocampal neurons (12). Noteworthy: Alzheimer Disease disproportionally affects women.

To notice, plasmalemmal VDAC and amyloid Aß, too, carry GxxxG peptide interaction motifs (2-4).

Concerning VDAC-1 agonists there are many data on low molecular weight agonists working on VDAC in varying settings, which may be helpful in studies on VRAC: DIDS, cholesterol, ATP, König's polyanion, dextran sulfate, Ga3+, Al3+, Zn2+, polyamines, compound 48/80, ruthenium red, fluoxetine, cisplatin, curcumin. Further studies looked for corresponding effect of peptides e.g. BH4-BClXL peptides, peptides including the free N-terminal part of VDAC-1 and amyloid Aβ peptides (4,9-16).

There is increasing evidence on interactions of VDAC-1 and proteineous modulators: e.g. α-synuclein shows high affinity interaction with voltage dependent anion channel, suggesting mechanisms of regulation and toxicity in Parkinson Disease (17). It has, furthermore, been shown that interaction of human plasminogen kringle 5 and plasmalemmal VDAC-1 links the channel to the extrinsic apoptotic pathway (18). Finally, an early study pointed to cancer cell cycle modulation by functional coupling between sigma-1 receptors and Cl- channels, here GxxxG motifs putatively playing a role (19,20).

Noteworthy, a SwissProt alignment of the LRC8A-D sequences shows two GxxxG motifs in a critical loop of LRC8E (Thinnes, unpublished).

Conclusion

While the expression of VDAC-1 in in the plasma membranes is beyond reasonable doubt (1-4) its function in this compartment is still in debate (5-20, 21-23).

VDAC-1 shows ubiquitous multi-toplogical expression, standing in outer mitochondrial membranes, the endoplasmic reticulum, as well as in the plasmalemma. To fulfill putatively varying functions in differing compartments, from the beginning on, my laboratory postulated proteineous channel modulators, which in varying heteromer complexes may adjust membrane-standing VDAC-1 to local needs.

Meanwhile, several of those come to the fore. VRAC/VSOAC candidates appear to be amongst them.

Finally, concerning medical relevance VDAC-1 complexes are involved in the pathogenesis of e.g. Cystic Fibrosis (13), Alzheimer Disease (3,4,12) and cancer (4).

References

1) De Pinto V, Messina A, Lane DJ, Lawen A. FEBS Lett. 2010 May 3;584(9):1793-9. doi: 10.1016/j.febslet.2010.02.049. Epub 2010 Feb 23. Review. PMID: 20184885 Free Article

2) Thinnes FP. Biochim Biophys Acta. 2015 Jun;1848(6):1410-6. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

3) Thinnes FP. Front Aging Neurosci. 2015 Sep 30;7:188. doi: 10.3389/fnagi.2015.00188. eCollection 2015. No abstract available. PMID: 26483684 Free PMC Article

4) Smilansky A, Dangoor L, Nakdimon I, Ben-Hail D, Mizrachi D, Shoshan-Barmatz V. J Biol Chem. 2015 Nov 5. pii: jbc.M115.691493. [Epub ahead of print] PMID: 26542804 Free Article

5) Morris AP, Frizzell RA. Am J Physiol. 1993 Apr;264(4 Pt 1):C977-85. PMID: 7682780

6) Blatz AL, Magleby KL. Biophys J. 1983 Aug;43(2):237-41. PMID: 6311302 Free PMC Article

7) Dermietzel R, Hwang TK, Buettner R, Hofer A, Dotzler E, Kremer M, Deutzmann R, Thinnes FP, Fishman GI, Spray DC, et al. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):499-503. PMID: 7507248 Free PMC Article

8) Schwiebert EM, Egan ME, Hwang TH, Fulmer SB, Allen SS, Cutting GR, Guggino WB. Cell. 1995 Jun 30;81(7):1063-73. PMID: 7541313 Free Article

9) Thinnes FP, Hellmann KP, Hellmann T, Merker R, Brockhaus-Pruchniewicz U, Schwarzer C, Walter G, Götz H, Hilschmann N. Mol Genet Metab. 2000 Apr;69(4):331-7. PMID: 10870851 10) Okada SF, O'Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC. J Gen Physiol. 2004 Nov;124(5):513-26. Epub 2004 Oct 11. PMID: 15477379 Free PMC Article

11a) Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. Cell Death Differ. 2005 Aug;12(8):1134-40. PMID: 15861186 Free Article

11b) Akanda N, Tofighi R, Brask J, Tamm C, Elinder F, Ceccatelli S. Cell Cycle. 2008 Oct; 7(20):3225-34. Epub 2008 Oct 20. PMID: 18927501

12a) Marin R, Ramírez CM, González M, González-Muñoz E, Zorzano A, Camps M, Alonso R, Díaz M. Mol Membr Biol. 2007 Mar-Apr;24(2):148-60. PMID: 17453421

12b) Herrera JL, Diaz M, Hernández-Fernaud JR, Salido E, Alonso R, Fernández C, Morales A, Marin R. J Neurochem. 2011 Mar;116(5):820-7. doi: 10.1111/j.1471-4159.2010.06987.x. Epub 2011 Jan 7. Review. PMID: 21214547 Free Article

13) Thinnes FP. Mol Genet Metab. 2014 Apr;111(4):439-44. doi: 10.1016/j.ymgme.2014.02.001. Epub 2014 Feb 13. Review. PMID: 24613483

14 Thinnes FP. PMID: 15781203 [PubMed - indexed for MEDLINE] Mol Genet Metab. 2005 Apr;84(4):378.

15) Thinnes FP. Mol Genet Metab. 2009 Jun;97(2):163. doi: 10.1016/j.ymgme.2009.01.014. Epub 2009 Feb 3. No abstract available. PMID: 19251445

16) Thinnes FP. Am J Physiol Cell Physiol. 2010 May;298(5):C1276. doi: 10.1152/ajpcell.00032.2010. No abstract available. PMID: 20413797 Free Article

17) Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL, Philpott CC, Lee JC, Bezrukov SM. J Biol Chem. 2015 Jul 24;290(30):18467-77. doi: 10.1074/jbc.M115.641746. Epub 2015 Jun 8. PMID: 26055708

18) Li L, Yao YC, Gu XQ, Che D, Ma CQ, Dai ZY, Li C, Zhou T, Cai WB, Yang ZH, Yang X, Gao GQ. J Biol Chem. 2014 Nov 21;289(47):32628-38. doi: 10.1074/jbc.M114.567792. Epub 2014 Oct 8. PMID: 25296756 Free PMC Article

19) Renaudo A, L'Hoste S, Guizouarn H, Borgèse F, Soriani O. J Biol Chem. 2007 Jan 26;282(4):2259-67. Epub 2006 Nov 22. PMID: 17121836 Free Article

20) Chu U, Ruoho AE. Mol Pharmacol. 2015 Nov 11. pii: mol.115.101170. [Epub ahead of print] PMID: 26560551 Free Article

21) Liu HT, Tashmukhamedov BA, Inoue H, Okada Y, Sabirov RZ. Glia. 2006 Oct;54(5):343-57. Erratum in: Glia. 2006 Dec;54(8):891.

22) Sabirov RZ, Merzlyak PG. Biochim Biophys Acta. 2012 Jun;1818(6):1570-80. doi: 10.1016/j.bbamem.2011.09.024. Epub 2011 Oct 1. Review. PMID: 21986486 Free Article

23) Pedersen SF, Klausen TK, Nilius B. Acta Physiol (Oxf). 2015 Apr;213(4):868-81. doi: 10.1111/apha.12450. Epub 2015 Jan 28.

On 2015 Nov 28, Friedrich Thinnes commented:

Arguments for plasmalemmal VDAC-1 to form the channel part of VRAC

The inclusion of VDAC-1 = voltage dependent anion channel of isotype-1 into the plasma membrane of mammalian cells was first demonstrated in 1989, this by its immuno-topochemical flagging on human B lymphocyte, and those data were meanwhile corroborated by several laboratories using manifold approaches world wide (1-4).

Concerning the function of plasmalemmal VDAC-1 (5-9) it has been shown that the channel is involved in cell volume regulation. Cell outside applied monoclonal mouse anti-human type-1 porin antibodies blocked the RVD of HeLa cells, proving that VDAC-1 is involved in the process. HeLa cells pre-incubated with the antibodies dramatically increased their volume within about 1 min after a stimulus by hypotonic Ringer solution, but did not move backward towards their starting volume, thus indicating abolished RVD.

To notice, corresponding blocking effects were induced by the established anion channel inhibitor DIDS or BH4BClXL peptides, respectively. Video camera monitoring of cell size over time was used in this direct and noninvasive approach (9; www.futhin.de Supplement 1). Corroboration of these data came from the laboratory of Dr. R. Boucher (10) using VDAC knock out mice, this study, furthermore, pointing to the channel as an ATP pathway.

First data concerning the involvement of plasmalemmal VDAC-1 in the apoptotic process came from Dr. F. Elinder´s laboratory, demonstrating that opening of plasma membrane voltage-dependent anion channels (VDAC) precedes caspase activation in neuronal apoptosis induced by toxic stimuli (11). In line, the laboratory of Dr. Raquel Marin demonstrated that voltage dependent anion channel (VDAC-1) participates in amyloid Aß-induced toxicity and also interacts with the plasma membrane estrogen receptor alpha (mERa) in septal and hippocampal neurons (12). Noteworthy: Alzheimer Disease disproportionally affects women.

To notice, plasmalemmal VDAC and amyloid Aß, too, carry GxxxG peptide interaction motifs (2-4).

Concerning VDAC-1 agonists there are many data on low molecular weight agonists working on VDAC in varying settings, which may be helpful in studies on VRAC: DIDS, cholesterol, ATP, König's polyanion, dextran sulfate, Ga3+, Al3+, Zn2+, polyamines, compound 48/80, ruthenium red, fluoxetine, cisplatin, curcumin. Further studies looked for corresponding effect of peptides e.g. BH4-BClXL peptides, peptides including the free N-terminal part of VDAC-1 and amyloid Aβ peptides (4,9-16).

There is increasing evidence on interactions of VDAC-1 and proteineous modulators: e.g. α-synuclein shows high affinity interaction with voltage dependent anion channel, suggesting mechanisms of regulation and toxicity in Parkinson Disease (17). It has, furthermore, been shown that interaction of human plasminogen kringle 5 and plasmalemmal VDAC-1 links the channel to the extrinsic apoptotic pathway (18). Finally, an early study pointed to cancer cell cycle modulation by functional coupling between sigma-1 receptors and Cl- channels, here GxxxG motifs putatively playing a role (19,20).

Noteworthy, a SwissProt alignment of the LRC8A-D sequences shows two GxxxG motifs in a critical loop of LRC8E (Thinnes, unpublished).

Conclusion

While the expression of VDAC-1 in in the plasma membranes is beyond reasonable doubt (1-4) its function in this compartment is still in debate (5-20, 21-23).

VDAC-1 shows ubiquitous multi-toplogical expression, standing in outer mitochondrial membranes, the endoplasmic reticulum, as well as in the plasmalemma. To fulfill putatively varying functions in differing compartments, from the beginning on, my laboratory postulated proteineous channel modulators, which in varying heteromer complexes may adjust membrane-standing VDAC-1 to local needs.

Meanwhile, several of those come to the fore. VRAC/VSOAC candidates appear to be amongst them.

Finally, concerning medical relevance VDAC-1 complexes are involved in the pathogenesis of e.g. Cystic Fibrosis (13), Alzheimer Disease (3,4,12) and cancer (4).

References

1) De Pinto V, Messina A, Lane DJ, Lawen A. FEBS Lett. 2010 May 3;584(9):1793-9. doi: 10.1016/j.febslet.2010.02.049. Epub 2010 Feb 23. Review. PMID: 20184885 Free Article

2) Thinnes FP. Biochim Biophys Acta. 2015 Jun;1848(6):1410-6. doi: 10.1016/j.bbamem.2015.02.031. Epub 2015 Mar 11. Review. PMID: 25771449

3) Thinnes FP. Front Aging Neurosci. 2015 Sep 30;7:188. doi: 10.3389/fnagi.2015.00188. eCollection 2015. No abstract available. PMID: 26483684 Free PMC Article

4) Smilansky A, Dangoor L, Nakdimon I, Ben-Hail D, Mizrachi D, Shoshan-Barmatz V. J Biol Chem. 2015 Nov 5. pii: jbc.M115.691493. [Epub ahead of print] PMID: 26542804 Free Article

5) Morris AP, Frizzell RA. Am J Physiol. 1993 Apr;264(4 Pt 1):C977-85. PMID: 7682780

6) Blatz AL, Magleby KL. Biophys J. 1983 Aug;43(2):237-41. PMID: 6311302 Free PMC Article

7) Dermietzel R, Hwang TK, Buettner R, Hofer A, Dotzler E, Kremer M, Deutzmann R, Thinnes FP, Fishman GI, Spray DC, et al. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):499-503. PMID: 7507248 Free PMC Article

8) Schwiebert EM, Egan ME, Hwang TH, Fulmer SB, Allen SS, Cutting GR, Guggino WB. Cell. 1995 Jun 30;81(7):1063-73. PMID: 7541313 Free Article

9) Thinnes FP, Hellmann KP, Hellmann T, Merker R, Brockhaus-Pruchniewicz U, Schwarzer C, Walter G, Götz H, Hilschmann N. Mol Genet Metab. 2000 Apr;69(4):331-7. PMID: 10870851 10) Okada SF, O'Neal WK, Huang P, Nicholas RA, Ostrowski LE, Craigen WJ, Lazarowski ER, Boucher RC. J Gen Physiol. 2004 Nov;124(5):513-26. Epub 2004 Oct 11. PMID: 15477379 Free PMC Article

11a) Elinder F, Akanda N, Tofighi R, Shimizu S, Tsujimoto Y, Orrenius S, Ceccatelli S. Cell Death Differ. 2005 Aug;12(8):1134-40. PMID: 15861186 Free Article

11b) Akanda N, Tofighi R, Brask J, Tamm C, Elinder F, Ceccatelli S. Cell Cycle. 2008 Oct; 7(20):3225-34. Epub 2008 Oct 20. PMID: 18927501

12a) Marin R, Ramírez CM, González M, González-Muñoz E, Zorzano A, Camps M, Alonso R, Díaz M. Mol Membr Biol. 2007 Mar-Apr;24(2):148-60. PMID: 17453421

12b) Herrera JL, Diaz M, Hernández-Fernaud JR, Salido E, Alonso R, Fernández C, Morales A, Marin R. J Neurochem. 2011 Mar;116(5):820-7. doi: 10.1111/j.1471-4159.2010.06987.x. Epub 2011 Jan 7. Review. PMID: 21214547 Free Article

13) Thinnes FP. Mol Genet Metab. 2014 Apr;111(4):439-44. doi: 10.1016/j.ymgme.2014.02.001. Epub 2014 Feb 13. Review. PMID: 24613483

14 Thinnes FP. PMID: 15781203 [PubMed - indexed for MEDLINE] Mol Genet Metab. 2005 Apr;84(4):378.

15) Thinnes FP. Mol Genet Metab. 2009 Jun;97(2):163. doi: 10.1016/j.ymgme.2009.01.014. Epub 2009 Feb 3. No abstract available. PMID: 19251445

16) Thinnes FP. Am J Physiol Cell Physiol. 2010 May;298(5):C1276. doi: 10.1152/ajpcell.00032.2010. No abstract available. PMID: 20413797 Free Article

17) Rostovtseva TK, Gurnev PA, Protchenko O, Hoogerheide DP, Yap TL, Philpott CC, Lee JC, Bezrukov SM. J Biol Chem. 2015 Jul 24;290(30):18467-77. doi: 10.1074/jbc.M115.641746. Epub 2015 Jun 8. PMID: 26055708

18) Li L, Yao YC, Gu XQ, Che D, Ma CQ, Dai ZY, Li C, Zhou T, Cai WB, Yang ZH, Yang X, Gao GQ. J Biol Chem. 2014 Nov 21;289(47):32628-38. doi: 10.1074/jbc.M114.567792. Epub 2014 Oct 8. PMID: 25296756 Free PMC Article

19) Renaudo A, L'Hoste S, Guizouarn H, Borgèse F, Soriani O. J Biol Chem. 2007 Jan 26;282(4):2259-67. Epub 2006 Nov 22. PMID: 17121836 Free Article

20) Chu U, Ruoho AE. Mol Pharmacol. 2015 Nov 11. pii: mol.115.101170. [Epub ahead of print] PMID: 26560551 Free Article

21) Liu HT, Tashmukhamedov BA, Inoue H, Okada Y, Sabirov RZ. Glia. 2006 Oct;54(5):343-57. Erratum in: Glia. 2006 Dec;54(8):891.

22) Sabirov RZ, Merzlyak PG. Biochim Biophys Acta. 2012 Jun;1818(6):1570-80. doi: 10.1016/j.bbamem.2011.09.024. Epub 2011 Oct 1. Review. PMID: 21986486 Free Article

23) Pedersen SF, Klausen TK, Nilius B. Acta Physiol (Oxf). 2015 Apr;213(4):868-81. doi: 10.1111/apha.12450. Epub 2015 Jan 28.