1) The core physics
For any ion channel, the instantaneous driving force is Vm−EionV_m – E_{\text{ion}} (Ohmic form: I≈g [Vm−Eion]I \approx g \,[V_m – E_{\text{ion}}]). For Ca²⁺, ECaE_{\text{Ca}} is strongly positive (~+120 mV), so hyperpolarizing the membrane (more negative VmV_m) increases Ca²⁺ influx through open Ca²⁺‑permeable channels; depolarizing VmV_m decreases it. For K⁺, EKE_K is negative (≈ −90 mV), so opening K⁺ channels tends to hyperpolarize VmV_m, which indirectly supports Ca²⁺ entry by maintaining a large ∣Vm−ECa∣|V_m – E_{\text{Ca}}|. This simple relation underlies multiple immune control points below. (Standard membrane biophysics.)
2) T cells: K⁺ channels set VmV_m; VmV_m sets Ca²⁺ entry; Ca²⁺ sets gene programs
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Kv1.3 and KCa3.1 are the dominant K⁺ channels in T cells. Their activity hyperpolarizes VmV_m and thereby sustains store‑operated Ca²⁺ entry through CRAC (ORAI1–STIM1) channels after T‑cell receptor (TCR) stimulation. Sustained cytosolic Ca²⁺ is required for calcineurin‑NFAT (and related NF‑κB) transcriptional programs that drive activation, cytokine production, and proliferation. Inhibiting Kv1.3/KCa3.1 depolarizes T cells, reduces the Ca²⁺ driving force, and attenuates activation. PMC+3PMC+3Nature+3
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Spatial control of CRAC. Upon TCR engagement, STIM1 (ER Ca²⁺ sensor) and ORAI1 reorganize into puncta at the immune synapse, producing microdomain Ca²⁺ signals whose amplitude and duration depend on VmV_m and K⁺ conductance. These signals time NFAT nuclear translocation and downstream gene expression. molbiolcell.org+1
Implication: In T cells, VmV_m is a control parameter: more negative VmV_m → more CRAC Ca²⁺ influx → stronger NFAT/NF‑κB activation; more positive VmV_m (depolarized) → the opposite. PMC+1
3) Phagocytes (neutrophils/macrophages): VmV_m enables the respiratory burst
During the NADPH‑oxidase respiratory burst, electrons move across the phagosomal/plasma membrane, which depolarizes the cell and acidifies the lumen. The voltage‑gated proton channel HVCN1 exports H⁺ to compensate charge and pH; without sufficient H⁺ conductance, the membrane over‑depolarizes and oxidase output collapses, sharply limiting superoxide generation and antimicrobial killing. Thus, appropriate VmV_m control enables a sustained respiratory burst. pnas.org+2PubMed+2
4) Macrophage polarization and metabolism: VmV_m as a gate on nutrient acquisition and signaling
The Kir2.1 inward‑rectifier K⁺ channel helps set resting VmV_m in macrophages. Modulating Kir2.1 (and thus VmV_m) controls surface retention of nutrient transporters, metabolic programming, and downstream CaMKII/ERK/NF‑κB signaling that biases inflammatory polarization states. In short, VmV_m influences whether macrophages adopt pro‑inflammatory vs. alternative activation profiles by regulating both ion flux and metabolic access. Nature+2Biologists Journals+2
5) Inflammasomes: K⁺ efflux, VmV_m, and danger signaling
Activation of the NLRP3 inflammasome typically requires K⁺ efflux (lowering intracellular [K⁺]); many stimuli (e.g., ATP via P2X7, ionophores) open cation pores that permit K⁺ exit. Because K⁺ movement changes both [K⁺]_i and VmV_m, channel and pore activities that favor K⁺ loss facilitate ASC speck formation, caspase‑1 activation, and IL‑1β/IL‑18 maturation. Thus, ion conductances that set VmV_m can gate inflammasome activity via K⁺ handling. PMC+2Frontiers+2
6) Migration and positioning: fields and VmV_m influence T‑cell behavior
Physiological‑strength electric fields (tens–hundreds mV/mm) bias human T‑cell migration direction (electrotaxis) and reduce activation markers under some conditions, demonstrating that modest bioelectric perturbations can modify functional outcomes in primary T cells. While electrotaxis concerns external fields, the underlying interface is VmV_m and its control of signaling pathways linked to motility and activation. Nature+1
7) Practical read‑outs and interventions
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What to measure: VmV_m (patch clamp/voltage‑sensitive dyes), CRAC currents, Ca²⁺ transient statistics (amplitude/intervals), NFAT nuclear translocation, ROS output (respiratory burst), inflammasome readouts (ASC specks, caspase‑1 activity), and cytokines.
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How to modulate: Kv1.3/KCa3.1 blockers or activators; HVCN1 modulation; extracellular K⁺ manipulations; P2X7 gating; Kir2.1 perturbations; and controlled field exposures to map VmV_m‑dependent thresholds. PMC+1
One‑line summary
Membrane potential is a first‑order control variable for immunity: K⁺ channels set VmV_m; VmV_m sets Ca²⁺ (and H⁺) flux; these fluxes set NFAT/NF‑κB transcription, respiratory‑burst capacity, inflammasome activation, and cellular polarization—thereby determining whether immune cells remain tolerant, become activated, or mount oxidative killing.
