Mechanism first explanation of how the plasma membrane potential controls immune responses

1) The core physics

For any ion channel, the instantaneous driving force is $Vm−EionV_m – E_{\text{ion}}$ (Ohmic form: $\approx g \,[V_m – E_{\text{ion}}]$ ). For Ca²⁺, $ECaE_{\text{Ca}}$ is strongly positive (~+120 mV), so hyperpolarizing the membrane (more negative $V_m$ ) increases Ca²⁺ influx through open Ca²⁺‑permeable channels; depolarizing $V_m$ decreases it. For K⁺, $E_K$ is negative (≈ −90 mV), so opening K⁺ channels tends to hyperpolarize $V_m$ , 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 $V_m$ ; $V_m$ sets Ca²⁺ entry; Ca²⁺ sets gene programs

Kv1.3 and KCa3.1 are the dominant K⁺ channels in T cells. Their activity hyperpolarizes $V_m$ 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
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 $V_m$ and K⁺ conductance. These signals time NFAT nuclear translocation and downstream gene expression. molbiolcell.org+1

Implication: In T cells, $V_m$ is a control parameter: more negative $V_m$ → more CRAC Ca²⁺ influx → stronger NFAT/NF‑κB activation; more positive $V_m$ (depolarized) → the opposite. PMC+1

3) Phagocytes (neutrophils/macrophages): $V_m$ 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 $V_m$ control enables a sustained respiratory burst. pnas.org+2PubMed+2

4) Macrophage polarization and metabolism: $V_m$ as a gate on nutrient acquisition and signaling

The Kir2.1 inward‑rectifier K⁺ channel helps set resting $V_m$ in macrophages. Modulating Kir2.1 (and thus $V_m$ ) controls surface retention of nutrient transporters, metabolic programming, and downstream CaMKII/ERK/NF‑κB signaling that biases inflammatory polarization states. In short, $V_m$ 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, $V_m$ , 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 $V_m$ , 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 $V_m$ can gate inflammasome activity via K⁺ handling. PMC+2Frontiers+2

6) Migration and positioning: fields and $V_m$ 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 $V_m$ and its control of signaling pathways linked to motility and activation. Nature+1

7) Practical read‑outs and interventions

What to measure: $V_m$ (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.
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 $V_m$ ‑dependent thresholds. PMC+1

One‑line summary

Membrane potential is a first‑order control variable for immunity: K⁺ channels set $V_m$ ; $V_m$ 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.

Source

Mechanism first explanation of how the plasma membrane potential controls immune responses

1) The core physics

2) T cells: K⁺ channels set VmV_mVm​; VmV_mVm​ sets Ca²⁺ entry; Ca²⁺ sets gene programs

3) Phagocytes (neutrophils/macrophages): VmV_mVm​ enables the respiratory burst

4) Macrophage polarization and metabolism: VmV_mVm​ as a gate on nutrient acquisition and signaling

5) Inflammasomes: K⁺ efflux, VmV_mVm​, and danger signaling

6) Migration and positioning: fields and VmV_mVm​ influence T‑cell behavior