Red Blood Cell Membrane Fluctuations and Shape Controlled by ATP-Induced Cytoskeletal Defects

Abstract

We show theoretically how adenosine 5'-triphosphate (ATP)-induced dynamic dissociations of spectrin filaments (from each other and from the membrane) in the cytoskeleton network of red blood cells (RBC) can explain in a unified manner both the measured fluctuation amplitude as well as the observed shape transformations as a function of intracellular ATP concentration. Static defects can be induced by external stresses such as those present when RBCs pass through small capillaries. We suggest that the partially freed actin at these defect sites may explain the activation of the CFTR membrane-bound protein and the subsequent release of ATP by RBCs subjected to deformations. Our theoretical predictions can be tested by experiments that measure the correlation between variations in the binding of actin to spectrin, the activity of CFTR, and the amount of ATP released.

Direct Cytoskeleton Forces Cause Membrane Softening in Red Blood Cells

“…In this case, the MS description remains valid for a q-dependent renormalized value of the bending modulus (in Eq. 1), which includes both additional contributions (14,25):…”

“…The transient binding capacity of these complexes depends on their phosphorylation state (10)(11)(12). This structural network endows the spectrin skeleton with the basic role of globally imparting structural rigidity to the cell membrane (13) and locally regulating its flexibility through reversible phosphorylation at the anchoring nodes (6,14). Indeed, the ability of RBCs to undergo reversible large deformations cannot be rationalized on the basis of a fixed connectivity of the cytoskeleton, but instead requires a model that attributes metabolically driven forces to active remodeling of the RBC cytoskeleton (6,14).…”

“…This structural network endows the spectrin skeleton with the basic role of globally imparting structural rigidity to the cell membrane (13) and locally regulating its flexibility through reversible phosphorylation at the anchoring nodes (6,14). Indeed, the ability of RBCs to undergo reversible large deformations cannot be rationalized on the basis of a fixed connectivity of the cytoskeleton, but instead requires a model that attributes metabolically driven forces to active remodeling of the RBC cytoskeleton (6,14). Therefore, RBC dynamics has been postulated to be metabolically regulated by continuous remodeling of the junctional nodes of the spectrin skeleton (6)(7)(8)14).…”

“…Indeed, the ability of RBCs to undergo reversible large deformations cannot be rationalized on the basis of a fixed connectivity of the cytoskeleton, but instead requires a model that attributes metabolically driven forces to active remodeling of the RBC cytoskeleton (6,14). Therefore, RBC dynamics has been postulated to be metabolically regulated by continuous remodeling of the junctional nodes of the spectrin skeleton (6)(7)(8)14). Under the optical microscope, normal RBCs experience large membrane undulations at the equatorial emplacement, a phenomenon originally referred to as the RBC flicker (15,16).…”

“…Recently, the RBC flickering phenomenon has been revisited (6,7,(22)(23)(24), providing an accurate catalog of static-averaged mechanical properties measured at different physiological conditions. The renewed interest in its metabolic causes and the possible functional consequences for RBC dynamics have motivated theoretical efforts hypothesizing the existence of ATP-dependent cytoskeleton forces (14,(25)(26)(27)). An adequate understanding of this hypothesis requires that a distinction be made between the active contribution of the cytoskeleton and passive thermal fluctuations, a problem that awaits definite experimentation.…”