Cell membranes are crowded and dynamic places. They constitute the first contact for all external stimuli that arrive at a cell, and are in charge of transmitting this information to the cell interior. This works through a cascade of metabolic steps, performed by several phospholipases, amongst other enzymes. Phospholipases degrade membrane components and form signal messengers, which transmit chemical messages to other actors of the signal transduction system. Through this process, membranes are transformed, changing both its chemical and physical properties. Those changes are “felt” by all the membrane components concerning global and complex information spreading.
In the last 25 years, scientists focused on the evidence that the lateral structure of cell membranes may be more complex than previously thought, and that the membranes may not be just the lipid sheet that surrounds cell components and constitutes its borders. This attention to the field resulted in the discovery of nano-size membrane structures, which show different physical properties than the rest of the membrane and would concentrate and enhance several cell functions. Those regions, called “lipid rafts” are susceptible to attack and desegregation by therapeutic agents (Fanani & Wilke, 2018). However, desegregating lateral structures is not the only way drugs can alter the function of the membrane at the signaling level.
Several enzymes of central relevance in lipid metabolism and cell signaling are highly regulated by the accumulation of phospholipase products. The rapid production of these molecules, imposes stress on the planar and relaxed structure of the membrane, introducing a high tendency to curve into non-planar lipid structures. This stimulus is essential for triggering the action of other membrane-bound proteins and intermediates in the lipid-mediated pathways (Davies, Epand, Kraayenhof, & Cornell, 2001).
Drugs, such as Miltefosine, can attack the membrane of the parasite Leishmania, with little effect on mammalian-cells. It is known that Miltefosine, a substance close related to natural phospholipids, penetrates the parasite cellular membrane disturbing lipid-dependent cell signaling pathways (Dorlo, Balasegaram, Beijnen, & De Vries, 2012). In recent work (Zulueta Díaz, Ambroggio, & Fanani, 2020), we demonstrate that Miltefosine can act by impairing the membrane restructuring induced by phospholipases, which explains its toxic effect on lipid metabolism. In other words, Miltefosine induces a relaxed, inactive planar membrane instead of the busy, stressed, and reactive membrane, which is essential for the living cell to sense the environment and grow.
Our results expose a novel dimension of membrane-targeting drug action, where not only the chemical, rheological, and lateral structure can be affected but the 3D structure of the cell membrane. It also opens up a new dimension to the search of new therapeutic agents based on its physical action on the membrane curvature.
Team members: Dr. Yenisleidy de las Mercedes Zulueta Díaz and Dr. Ernesto E. Ambroggio.
ReferencesDavies, S. M. a, Epand, R. M., Kraayenhof, R., & Cornell, R. B. (2001). Regulation of CTP: Phosphocholine cytidylyltransferase activity by the physical properties of lipid membranes: an important role for stored curvature strain energy. Biochemistry, 40(35): 10522–10531. Available at: http://doi.org/10.1021/bi010904c [Accessed: 20 Nov 2020].
Dorlo, T. P. C., Balasegaram, M., Beijnen, J. H., & De Vries, P. J. (2012). Miltefosine: A review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. Journal of Antimicrobial Chemotherapy, 67(11): 2576–2597. Available at: http://doi.org/10.1093/jac/dks275 [Accessed: 20 Nov 2020].
Fanani, M. L., & Wilke, N. (2018). Regulation of phase boundaries and phase-segregated patterns in model membranes. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1860(10): 1972–1984. Available at: http://doi.org/10.1016/j.bbamem.2018.02.023 [Accessed: 20 Nov 2020].
Zulueta Díaz, Y. de las M., Ambroggio, E. E., & Fanani, M. L. (2020). Miltefosine inhibits the membrane remodeling caused by phospholipase action by changing membrane physical properties. Biochimica et Biophysica Acta - Biomembranes, 1862(10): 183407. Available at: http://doi.org/10.1016/j.bbamem.2020.183407 [Accessed: 20 Nov 2020].