«Systems Biology and Physiology Reports:Issue #3»

Опубликовано 30 сентября 2021

Hubs and Webs in Platelet Intracellular Signalling

In this issue of Systems Biology and Physiology Reports A.A. Martyanov and M.A. Panteleev suggested a review on platelet intracellular signalling network, which is a second part in the discussion on the molecular relationships between platelet activation and responses [1]. The review contains seven thousands words and two hundred references and yet it is not complete, as there are still unclear parts in platelet signalling, especially in its inhibition [2-4]. In an effort to comprehend the platelet activation pattern, I drew a signalling scheme based on the review and data from other authors [2, 3].

Scheme of platelet intracellular signalling with focus on cytosolic calcium as a “Hub”. Cytosolic calcium concentration is given in the shades of red. Almost all types of platelet receptor agonists lead to activation of phospholipase C (PLC), followed by calcium release from intracellular stores (DTS). Calcium concentration is rapidly reduced by calcium-dependent ATPases (SERCA and PMCA). Also, it could be reduced by binding with some buffering proteins, including its effector-proteins (indicated with red dots). Platelet mitochondria also can function as a calcium buffer and, simultaneously, be regulated by calcium concentration. Direct activation is shown by solid green arrows, direct inhibition - by solid red arrows. Indirect interactions are shown by dashed lines. Abbreviations. AC – adenylate cyclase, α2AAR - α2A-adrenergic receptor, CDGEF - CalDAGGEFI, COX – cyclooxygenase, DAG - diacylglycerol, DTS - dense tubular system, Fbg – fibrinogen, IP3R - receptor for inositol-1,4,5-trisphosphate (IP3), Mit - a mitochondrion, mPTP - mitochondrial permeability transition pore, NCLX - mitochondrial sodium/calcium exchanger, OCS - open canalicular system, P2Y - purinergic receptor, PAR - protease-activated receptor, PIP2 - phosphoinositol-4,5-bisphosphate, PIP3 - phosphoinositol-3,4,5-trisphosphate, PI(P)n – phosphoinositides, PKA – protein kinase A, PKG – protein kinase G, PKC – protein kinase C, PL – phospholipid, PLA2 – phospholipase A2, PMCA - plasma membrane calcium ATPase, PR - PGI2 receptor, P-Tyr – phosphorylated tyrosine residue, SERCA - sarcoplasmic/endoplasmic reticulum calcium ATPase, sGC – soluble guanylate cyclase, TR - thromboxane A2 (TxA2) receptor, TRPC - transient receptor potential channel, UNI - mitochondrial uniporter, vWF – von Willebrand Factor, Y-Pase – tyrosine phosphatase.

Platelet functional responses and signalling: the molecular relationship. Part 2: receptors.

Small, non-nuclear cells, platelets, are primarily designed to form aggregates when blood vessels are damaged, stopping bleeding. To perform this function, platelets can implement several functional responses induced by various agonists and coordinated by a complex network of intracellular signaling triggered by a dozen of different receptors. This review, the second in a series, describes the known intracellular signaling pathways induced by platelet receptors in response to canonical and rare agonists. Particular focus will be on interaction points and “synergy” of platelet activation pathways and intermediate or “secondary” activation mediators that transmit a signal to functional manifestations.

Different degrees of the platelet activation in hemostasis. Upon weak stimulation, platelets pass into a weakly activated state, in which there is no clustering of platelet integrins and no significant change in the shape of platelets. This weak activation is reversible, and it corresponds to the state of platelets in the outer layers ("coat") of the thrombus. Upon stronger activation, platelet shape significantly changes. Platelets become irreversibly activated and aggregate. The secretion of platelet granules also occurs. At the maximum degree of activation, platelet mitochondria collapse, and platelets pass into a procoagulant state, exposing phosphatidylserine, which significantly accelerates blood plasma coagulation.
2 669
#platelets#intracellular signaling#physiology

A minimal mathematical model of neutrophil pseudopodium formation during chemotaxis

The directed movement of neutrophils is provided by the rapid polymerization of actin with the formation of a protrusion growing forward. In our previous work we observed impaired neutrophil movement for patients with Wiskott-Aldrich syndrome (WAS) compared to healthy donors.

In this work, we set out to explain the impairment of neutrophil chemotaxis in patients by observation and computer modeling of the linear growth rates of the anterior pseudopodia. The neutrophil chemotaxis was observed by means of low-angle fluorescent microscopy in parallel-plate flow chambers. The computational model was constructed as a network-like 2D stochastic polymerization of actin guided by the proximity of cell membrane with branching governed by Arp2/3 and WASP proteins.

The observed linear velocity of neutrophil pseudopodium formation was 0.22 ± 0.04 μm/s for healthy donors and 0.23 ± 0.08 μm/s for WAS patients. The model described the velocity of the pseudopodium formation for healthy donors well. For the description of WAS patients data, a variation of branching velocity (governed by WASP) by an order of magnitude was applied, which did not significantly alter the linear protrusion growth velocity.

We conclude that the proposed mathematical model of neutrophil pseudopodium formation could describe the experimental data well, but the data on overall neutrophil movement could not be explained by the velocities of the pseudopodium growth.

Scheme of the computational model. (A) The scheme of stochastic events and species included in the model. A single F-actin filament is assumed to be straight and to be divided into segments. Each segment can be considered to be an actin monomer. New G-actin molecules can attach to and detach from the filament “barbed” end. It is assumed that the child filament begins to grow from the middle between two segments of F-actin at the angle of 70o.  If there is a branch growing from the F-actin segments, they are considered occupied and no branching can occur there. (B) The spatial restrictions on the filament growth and branching. The filaments can branch if the distance from the cell membrane is lesser than D. Filaments can grow if the distance from the cell membrane is lesser than H, where H > D.
#cytoskeleton#neutrophils#actin#chemotaxis#Wiskott-Aldrich syndrome

Overview of the neutralizing antibody and memory B cell response kinetics in SARS-CoV-2 convalescent and/or mRNA vaccinated individuals.

COVID-19 pandemics triggered by the SARS-CoV-2 virus have caused millions of deaths worldwide and have led to expedited developments of various effective vaccines that, if administered, could prevent and/or circumvent the infection and reduce the death toll. Since the start of the pandemics multiple research groups around the world have been involved in the analysis of immune responses of various human cohorts to the SARS-CoV-2 infection and vaccines. Now, over 1.5 years later, the scientific community has accumulated extensive data about both the development of an immune response to SARS-CoV-2 following infection, as well as its rate of fading off. Kinetic analysis of the immune response generated by vaccines is also emerging, enabling the possibility of making comparisons and predictions. In this review we will focus on the comparing B cell and antibody immune responses to the SARS-CoV-2 infection as opposed to mRNA vaccines for the SARS-CoV-2 S-protein, which have been utilized to immunize hundreds of millions of people and analyzed in multiple studies.

#B-cells#COVID-19#vaccines#immune response