Placing Ion Channels into a Signaling Network of T Cells: From Maturing Thymocytes to Healthy T Lymphocytes or Leukemic T Lymphoblasts

Figure 4

Ca²⁺ influx network in T cells. Channels, marked with asterisks, are overexpressed or present exclusively in T-ALL. Central is activation of CRAC- (Orai1+STIM1) mediated Ca²⁺ influx. Activation of PLC (e.g., via the T cell receptor) causes cleavage of PIP₂ with the production of DAG and soluble IP₃; the latter activates IP₃-receptor Ca²⁺ release channels of the endoplasmic reticulum. Ca²⁺ store depletion is sensed by specialized transmembrane sensors (STIM1), which oligomerize and move to special contact zones of ER with the plasma membrane, where they physically interact with the channel-forming proteins (Orai), forcing them to form active Ca²⁺ selective channel (CRAC), which mediates Ca²⁺ influx. Operation of CRAC is further modulated by the activity of other channels, which affects the membrane polarization and intracellular Ca²⁺. Voltage-independent Ca²⁺-dependent K⁺ channels potentiate CRAC-mediated Ca²⁺ influx, lowering the membrane potential, thus increasing the driving force for Ca²⁺ uptake. Conversely, channels with a predominant Na⁺ permeability (TRPM4) cause membrane depolarization and abrogation of the Ca²⁺ influx. Depending on the channel selectivity high Ca²⁺ (e.g., TRPV5) or indiscriminate Ca²⁺/Na⁺ (e.g., TRPC) as well as (when applicable) on the nature of the feedback (positive or negative, see respective loops) via Ca²⁺ and on the context (differential ways for the activation of particular ion channel), overall Ca²⁺ signal can be positively or negatively modulated. An idealized Ca²⁺ response to a mitogen stimulation, which contains both oscillatory and monotonous increase components, evidencing a feedback regulation via Ca²⁺, is given as an example. Ways of the channels’ activation are summarized below. From the left to the right: Ca_v (voltage-dependent Ca²⁺ channels), P2X (purinergic ionotropic receptors), TRP (transient receptor potential channels), Orai-STIM1 (CRAC, Ca²⁺ release-activated Ca²⁺ channel), K_Ca (Ca²⁺-activated K⁺ channels), TRESK (TWIK-like spinal cord K⁺ channel), and CaM (calmodulin).