Channels, Transporters, and Receptors at Membrane Contact Sites

Abstract

Membrane contact sites (MCSs) are specialized regions where two or more organelle membranes come into close apposition, typically separated by only 10-30 nm, while remaining distinct and unfused. These sites play crucial roles in cellular homeostasis, signaling, and metabolism. This review focuses on ion channels, transporters, and receptors localized to MCSs, with particular emphasis on those associated with the plasma membrane and endoplasmic reticulum (ER). We discuss the molecular composition and functional significance of these proteins in shaping both organelle and cellular functions, highlighting their importance in excitable cells and their influence on intracellular calcium signaling. Key MCSs examined include ER-plasma membrane, ER-mitochondria, and ER-lysosome contacts. This review addresses our current knowledge of the ion channels found within these contacts, the dynamic regulation of MCSs, their importance in various physiological processes, and their potential implications in pathological conditions.

Keywords: IP3 receptor; calcium (Ca2+); calcium-induced calcium release (CICR); endoplasmic reticulum (ER); ion channels; junctophilin (JPH); large conductance Ca2+-activated K+ channel (BKCa); membrane contact sites (MCS); neurodegeneration; niemann-Pick type C1 (NPC1); orai; ryanodine receptors (RyR); stromal interaction molecule (Stim); transient receptor potential cation channel subfamily M member 4 (TRPM4); voltage-gated calcium channel (CaV); voltage-gated potassium channel (KV).

Figure 1.

Molecular composition of a membrane contact site. (A) Typical components present within a MCS include (left to right): membrane tether, Ca²⁺-handling proteins, and/or lipid-transfer protein. Green triangles represent Ca²⁺ gradient between extracellular or luminal and intracellular Ca²⁺ (∼100-200 nM) concentrations. (B) Role of Ca²⁺-handling proteins at MCS. Ca²⁺-handling proteins facilitate the transduction (conversion of an electrical signal or ligand into a Ca²⁺ signature), amplification, propagation (local elevations in Ca²⁺ at MCS can exert broad influence through the cell), and termination.

Figure 2.

Ion channels in SR-PM MCS in muscle cells. (A) Skeletal muscle. Left: representation of triad organization in skeletal muscle cells and molecular components Right: Structural and functional organization of ion channels that facilitate CICR in skeletal muscle cells. (B) Same as (A) only cardiac muscle. (C) Same as A, B only smooth muscle.

Figure 3.

Ion channels in SR-PM MCS in neurons. (A) Left: absence of phosphorylation in K_V2.1s PCR domain results in non-clustered K_V2.1 channels that regulate PM electrical excitability. Right: phosphorylation of K_V2.1 facilitates interactions with ER VAP proteins, recruitment of Ca_V1.2 channels and RyR2, and an increase in Ca²⁺ entry into neurons leading to CICR at neuronal MCSs. (B) Activity-dependent influx of Ca²⁺ through Ca_V1.3 channels induces CICR from RyR2 which activates KCa3.1 and hyperpolarizes the membrane potential. (C) Similar mechanism as (B) only with Ca_V2.1–RyR–BKCa signaling axis.

Figure 4.

Ion channels in ER–mitochondrial MCS. Tethers and ion channels present at ER–mitochondrial MCS influence mitochondrial Ca²⁺ levels to regulate bioenergetics and apoptosis.