Abstract
The amyloidoses consist of human and animal chronic, progressive, and sometimes fatal diseases that are characterized by the deposition of insoluble proteinaceous amyloid fibrils in various tissues. Despite the biochemical diversity of amyloids, they share certain properties. The amphipathic and the charged nature of many amyloid-forming peptides point to their intrinsic ability to form diverse β-sheet-based aggregates and channel types in negatively charged membranes. We hypothesize that the formation of heterogeneous channels represents a common cytotoxic mechanism that accentuates the changes in the signal transduction that underlie amyloid-induced cell malfunction. One group of amyloid-forming peptides that could mediate their action via the formation of heterogeneous channels includes the extensively examined prions and amyloid β protein that are associated with conformational neurodegenerative diseases. The aim of this study is to examine heterogeneous channels formed in bilayers with amyloid-forming peptides as a common mechanism of malfunction of signal transduction. the observed amyloid-formed channel types include the following. (1) Natriuretic peptides: (i) 68-pS H2O2- and Ba2+-sensitive channel with fast kinetics. The fast channel had three modes (spike mode, burst mode, and open mode), which differ in their kinetics but not in their conductance properties; (ii) a 273-pS inactivating large conductance channel; and (iii) a 160-pS transiently activated channel. (2) Prions: (i) a 140-pS GSSG- and TEA-sensitive channel with fast kinetics; (ii) a 41-pS dithiothreitol (DTT)-sensitive channel with slow kinetics; (iii) a 900 to 1444-pS large channel. (3) Amyloid β protein: (i) a 17 to 63-pS AßP [1–40]-formed “bursting” fast cation channel, (ii) the AßP [1–40]-formed “spiky” fast cation channel with a similar kinetics to the “bursting” fast channel except for the absence of the long intraburst closures, (iii) 275-pS AßP[1–40]-formed medium conductance channel, and (iv) 589- to 704-pS AßP[1–40]-formed inactivating large conductance channel. This heterogeneity is one of the most common features of these charged cytotoxic amyloid-formed channels, reflecting these channels' ability to modify multiple cellular functions. Although the diversity of these aggregated-peptideformed channels may indicate that a stochastic mechanism governs their formation, the fact that certain channel types are often observed point to preferential channel protein conformations. In addition, the fact that other amyloids have similar structural properties (e.g. hydrophobicity, charged residues, and β-structural linkages, suggests that, despite the intrinsic ability to form diverse conformations, certain conformations and, hence, certain channel types could be a common pathologic conformation among these amyloid-forming peptides. It is concluded that conformation-based channel diversity is an important mechanism for enhancing the toxicity of amyloid-forming peptides. The cytotoxic nature of these self-associated β-based protein channels suggests that under normal physiological conditions cells employ well-evolved protective mechanisms against seeding and/or propagation of channel-forming peptides; for example, (a) compartmentalization of these peptides as membrane bound in internal vesicles and/or (b) degradation of these peptides by enzymes. The pharmacological diversity of the amyloid-forming channels implies that multiple therapeutic interventions may be necessary for blocking and reversing heterogeneous channel formations and preventing their associated diseases.
Similar content being viewed by others
References
Kourie, J. I., Henry, C. L., and Farrelly, P. V. (2001) Diversity of amyloid β protein fragment [1–40]-formed channels. Cell. Mol. Neurobiol. 21, 255–284.
Arispe, N., Pollard, H. B., and Rojas, E. (1993) Giant multilevel cation channels formed by alzheimer disease amyloid β-protein. Proc. Natl. Acad. Sci. USA 90, 10,573–10,577.
Arispe, N., Rojas, E., and Pollard, H. B. (1993) Alzheimer disease amyloid β protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc. Natl. Acad. Sci. USA 90, 567–571.
Arispe, N., Pollard, H. B., and Rojas, E. (1994) β-amyloid Ca2+-channel hypothesis for neuronal death in Alzheimer disease. Mol. Cell. Biochem. 140, 119–125.
Arispe, N., Pollard, H. B., and Rojas, E. (1996) Zn2+ interaction with Alzheimer amyloid β protein calcium channels. Proc. Natl. Acad. Sci. USA 93, 1719–1715.
Durell, S. R., Guy, H. R., Arispe, N., Rojas, E., and Pollard, H. B. (1994) Theoretical models of the ion channel structure of amyloid beta-protein. Biophys. J. 67, 137–145.
Pollard, H. B., Arispe, N., and Rojas, E. (1995) Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity. Cell. Mol. Neurobiol. 15, 513–526.
Kawahara, M., Arispe, N., Kuroda, Y., and Rojas, E. (1997) Alzheimer's disease amyloid beta-protein forms Zn2+-sensitive cation-selective channels across excised membrane patches from hypothalamic neurons. Biophys. J. 73, 67–75.
Kawahara, M., Kuroda, Y., Arispe, N., and Rojas, E. (2000) Alzheimer's disease β-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in hypothalamic GnRH neuronal cell line. J. Biol. Chem. 275, 14,077–14,063.
Mirzabekov, T. A., Lin, M. C., Yuan, W. L., Marshall, P. J., Carman, M., Tomaselli, K., et al. (1994) Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide. Biochem. Biophys. Res. Commun. 202, 1142–1148.
Hirakura, Y., Lin, M. C., and Kagan, B. L. (1999) Alzheimer amyloid Aβ1–42 channels: effects of solvent, pH, and Congo Red. J. Neurosci. Res. 57, 458–466.
Hirakura, Y., Yiu, W. W., Yamamoto, A., and Kagan, B. L. (2000) Amyloid peptide channels: blockade by zinc and inhibition by congo red. Amyloid 7, 194–199.
Kourie, J. I. (2001). Mechanisms of amyloid-induced modification in the electrical properties of membranes. Cell. Mol. Neurobiol. 21, 173–213.
Catterall, W. (1992) Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 72, S15-S48.
Kourie, J. I. (2001) Mechanisms of prion-induced modification in membrane transport systems. Chem. Biol. Interact. 138, 1–26.
Bush, A. I., Pettingell, W. H., Jr, Paradis, M. D., and Tanzi, R. E. (1994). Modulation of A beta adhesiveness and secretase site cleavage by zinc. J. Biol. Chem. 269, 12,152–12,158.
Kourie, J. I., and Culverson, A. (2000) Prion peptide fragment PrP[106–126] forms distinct cation channel types. J. Neurosci. Res. 62, 120–133.
Lin, M-C., Mirzabekov, T., and Kagan, B. L. (1997) Channel formation by a neurotoxic prion protein fragment. J. Biol. Chem. 272, 44–47.
Manunta, M., Kunz, B., Sandmeier, E., Christen, P., and Schindler, H. (2000) Reported channel formation by prion protein fragment 106–126 in planar lipid bilayer cannot be reproduced. FEBS Lett. 474, 252–256.
Kourie, J. I., Farrelly, P. V., and Henry, C. L. (2001) Channel activity of deamidated isoforms of prion protein fragment 106–126 in planar lipid bilayers. J. Neurosci. Res. 66, 214–220.
Kunz, E., Sandmeier, E., and Christen, P. (1999) Neurotoxicity of prion peptide 106–126 not confirmed. FEBS Lett. 458, 65–68.
Chapron, Y., Peyrin, J-M., Crouzy, S., Jaegly, A., and Dormont, D. (200) Theoretical analysis of the implication of PrP in neuronal death during transmissible subacute spongiform encephalopathies: hypothesis of a PrP oligomeric channel. J. Theor. Biol. 204, 103–111.
Kourie, J. I. (1999) Calcium dependence of C-type natriuretic peptide-formed fast K+ channel. Am. J. Physiol. 277, C43-C50.
Jobling, M. F., Huang, X., Stewart, L. R., Barnham, K. J., Curtain, C., Volitakis, I., et al. (2001) Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106–126. Biochemistry 40, 8073–8084.
Sandmeier, E., Kunz, E., Hunziker, P., Sack, R., and Christen, P. (1999) Spontaneous deamidation and isomerization of Asn 108 in prion peptide 106–126 and in full-length prion protein. Biochem. Biophys. Res. Commun. 261, 578–583.
Rauk, A., and Armstrong, D. A. (2000) Influence of β-sheet structure on the susceptibility of proteins to backbone oxidative damage: preference of αC-central radical formation at glycine residues of antiparallel β-sheets. J. Am. Chem. Soc. 122, 4185–4192.
Brown, D. R., Wong, B. S., Hafiz, F., Clive, C., Haswell, S. J., and Jones, I. M. (1999) Normal prion protein has an activity like that of super-oxide dismutase. Biochem. J. 344, 1–5.
Brown, D. R., Clive, C., and Haswell, S. J. (2001) Antioxidant activity related to copper binding of native prion protein. J. Neurochem. 76, 69–76.
Florio, T., Grimaldi, M., Scorziello, A., Salmona, M., Bugiani, O., Tagliavini, F., et al. (1996) Intracellular calcium rise through L-type calcium channels, as molecular mechanism for prion protein fragment 106–126-induced astroglial proliferation. Biochem. Biophys. Res. Commun. 228, 397–405.
Barrow, P. A., Holmgren, C. D., Tapper, A. J., and Jefferys, J. G. (1999) Intrinsic physiological and morphological properties of principal cells of the hippocampus and neocortex in hamsters infected with scrapie. Neurobiol. Dis. 6, 406–423.
Kojima, M., Minamino, N., Kangawa, K., and Matsuo, H. (1990) Cloning and sequence analysis of a cDNA encoding precursor for rat C-type natriuretic peptide (CNP). FEBS Lett. 276, 209–213.
Sudoh, T., Minamino, N., Kenji, K., and Matsuo, H. (1990) C-Type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem. Biophys. Res. Commun. 168, 863–870.
Komatsu, Y., Nakao, K., Suga, S., Ogawa, Y., Mukoyama, M., Arai, H., et al. (1991) C-Type natriuretic peptide (CNP) in rats and humans. Endocrinology 129, 1104–1106.
Mukoyama, M., Nakao, K., Hosoda, K., Suga, S., Saito, Y., Ogawa, Y., et al. (1991) Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J. Clin. Invest. 87, 1402–1412.
Suga, S., Itoh, H., Komatsu, Y., Ogawa, Y., Hama, N., Yoshimasa, T., et al. (1993) Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells: evidence for CNP as a novel autocrine paracrine regulator from endothelial cells. Endocrinology 133, 3038–3041.
Suga, S., Nakao, Hosoda, K., Mukoyama, M., Ogawa, Y., Shirakami, G., et al. (1992) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130, 229–239.
de Plater, G. M., Martin, R. L., and Milburn, P. J. (1995) A pharmacological and biochemical investigation of the venom from the platypus (Ornithorhynchus anatinus). Toxicon 33, 157–169.
de Plater, G. M., Martin, R. L., and Milburn, P. J. (1998a) The natriuretic peptide (ovCNP) from platypus (Ornithorhynchus anatinus) venom relaxes the isolated rat uterus and promotes oedema and mast cell histamine release. Toxicon 36, 847–857.
Suga, S., Nakao, K., Itoh, H., Komatsu, Y., Ogawa, Y., Hama, N., et al (1992) Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of “vascular natriuretic peptide system”. J. Clin. Invest. 90, 1145–1149.
Murayama, N., Hayashi, M., Ohi, H., Ferreira, L. A. F., Hermann, V., Saito, H., et al. (1997) Cloning and sequence analysis of a Bothrops jararaca cDNA encoding a precursor of seven bradykinin-potentiating peptides and a C-type natriuretic peptide. Proc. Nat. Acad. Sci. USA 94, 1189–1193.
Kourie, J. I. (1999) Synthetic mammalian C-type natriuretic peptide forms large cation channels. FEBS Lett. 445, 57–62.
Kourie, J. I. (1999) Characterisation of a C-type natriuretic peptide (CNP-39)-formed cation-selective channel from platypus (Ornithrhynchus anatimus) venom. J. Physiol. 518, 359–369.
Stingo, A. J., Clavell, A. L., Arthus, L., and Burnett, J. C., Jr. (1992) Cardiovascular and renal actions of C-type natriuretic peptide. Am. J. Physiol. 262, H308-H312.
Wei, C. M., Hu, S., Miller, V. M., and Burnett, J. C. J. (1994) Vascular actions of C-type natriuretic peptide in isolated porcine coronary arteries and coronary vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 205, 765–771.
White, R. E., Lee, A. B., Shcherbatko, A. D., Lincoln, T. M., Schonbrunn, A., and Armstrong, D. L. (1993) Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation. Nature 361, 263–266.
Kelley, T. J., Cotton, C. U., and Drumm, M. L. (1997) In vivo activation of CFTR-dependent chloride transport in murine airway epithelium by CNP. Am. J. Physiol. 273, L1065-L1072.
Kelley, T. J., Cotton, C. U., and Drumm, M. L. (1998) Regulation of amiloride-sensitive sodium absorption in murine airway epithelium by C-type natriuretic peptide. Am. J. Physiol. 273, L990-L996.
Solomon, R., Protter, A., McEnroe, G., Porter, J. G., and Silva, P. (1992) C-Type natriuretic peptides stimulate chloride secretion in the rectal gland of Squalus acanthias. Am. J. Physiol. 262, R707-R771.
Kurochkin, I. V. (1998) Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS Lett. 427, 153–156.
Takemura, G., Takatsu, Y., Doyama, K., Itoh, H., Saito, Y., Koshiji, M., et al. (1998) Expression of atrial and brain natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis. J. Am. Coll. Cardiol. 31, 754–765.
Takahashi, M., Hoshii, Y., Kawano, H., Gondo, T., Yokota, T., Okabyashi, H., et al. (1998) Ultrastructural evidence for the formation of amyloid fibrils within cardiomyocytes in isolated atrial amyloid. Amyloid 5, 35–42.
Barger, S. W. and Mattson, M. P. (1995) The secreted form of the Alzheimer's beta-amyloid precursor protein stimulates a membrane-associated guanylate cyclase. Biochem. J. 311, 45–47.
Jan, L. Y. and Jan, Y. H. (1997) Receptor-regulated ion channels. Curr. Opin. Cell Biol. 9, 155–160.
Hirakura, Y. and Kagan, B. L. (1999) Channel formation in the pathogenesis of Alzheimer's disease and other amyloidoses. Einstein Qu. J. Biol. Med. 16, 124–129.
Hama, N., Itoh, H., Shirakami, G., Suga, S., Komatsu, Y., Yoshimasa, T., et al. (1994) Detection of C-type natriuretic peptide in human circulation and marked increase of plasma CNP level in septic shock patients. Biochem. Biophys. Res. Comm., 198, 1177–1182.
de Plater G. M., Martin, R. L., and Milburn, P. J. (1998) A C-Type natriuretic peptide from the venom of the platypus (Ornithorhynchus anatinus): structure and pharmacology. Comp. Biochem. Physiol. C 120, 99–110.
de Plater, G. M. (1998) Fractionation, primary structural characterisation and biological activities of polypeptides from the venom of the platypus (Ornithorhynchus anatinus). Ph.D. thesis, Australian National University. Canberra, Australia.
Kourie, J. I. and Rive, M. J. (1999) Role of natriuretic peptides in ion transport mechanisms. Med. Res. Rev. 19, 75–94.
Hille, B. (1992) Ionic Channels of Excitable Membranes (Hille, B., ed.), Sinaure Associates, Sunderland, MA.
Merrill, A. R., Steer, B. A., Prentice, G. A., Weller, M. J., and Szabo, A. G. (1997) Identification of a chameleon-like pH-sensitive segment within the colicin E1 channel domain that may serve as the pH-activated trigger for membrane bilayer association. Biochemistry 36, 6874–6884.
Minn, A. J., Velez, P., Schendel, S. L., Liang, H., Muchmore, S. W., Fesik, S. W., et al. (1997) Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 385, 353–357.
Hinrichesn, R. D. (1993) Calcium-Dependent Potassium Channels R. G. Landes Company, Austin, TX.
Pallotta, B. (1985) N-Bromoacetamide removes a calcium-dependent component of channel opening from calcium-activated potassium channels in rat skeletal muscle. J. Gen. Physiol. 86, 601–611.
Marrion, N. V. and Tavalin, S. J. (1998) Selective activation of Ca2+-activated K+ channels by colocalized Ca2+ channels in hippocampal neurons. Science 395, 900–905.
Yagi, S., Becker, P. C., and Fay, F. S. (1988) Relationship between force and Ca2+ concentration in smooth muscle as revealed by measurement on single cells. Proc. Natl. Acad. Sci. USA 85, 4109–4113.
Koller, K. J., Lowe, D. G., Bennett, G. L., Minamino, W., Kangawa, K., Matsuo, H., et al. (1991) Selective activationof the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 252, 120–123.
Morita, H., Hagike, M., Horiba, T., Miyake, K., Ohyama, H., Yamaouchi, H., et al. (1992) Effects of brain natriuretic peptide and C-type natriuretic peptide infusion on urine flow and jejunal absorption in anesthetized dogs. Jpn. J. Physiol. 42, 349–353.
Kourie, J. I., Hanna, E. A., and Henry, C. L. (2001). Properties of alpha human atrial natriuretic peptide (α-hANP)-formed ion channels. Can. J. Physiol. Pharmacol. 79, 654–664.
Mirzabekov, T. A., Lin, M. C., and Kagan, B. L. (1996) Pore formation by the cytotoxic islet amyloid peptide amylin. J. Biol. Chem. 271, 1988–1992.
McLean, L. R. and Balasubramaniam, A. (1992) Promotion of beta-structure by interaction of diabetes associated polypeptide (amylin) with phosphatidylcholine. Biochem. Biophys. Acta 1122, 317–320.
Charge, S. B., de Koning, E. J., and Clark, A. (1995) Effect of pH and insulin on fibrillogenesis of islet amyloid polypeptide in vitro. Biochemistry 34, 14,588–14,593.
Janson, J., Ashley, R. H., Harrison, D., McIntyre, S., and Butler, P. C. (1999) The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48, 491–498.
Munoz, F. J. and Inestrosa, N. C. (1999). Neurotoxicity of acetylcholinesterase amyloid beta-peptide aggregates is dependent on the type of Abeta peptide and the AchE concentration present in the complexes. FEBS Lett. 450, 205–209.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kourie, J.I., Culverson, A.L., Farrelly, P.V. et al. Heterogeneous amyloid-formed ion channels as a common cytotoxic mechanism. Cell Biochem Biophys 36, 191–207 (2002). https://doi.org/10.1385/CBB:36:2-3:191
Issue Date:
DOI: https://doi.org/10.1385/CBB:36:2-3:191