Receptors and Membrane Biology

Membrane receptors and transporters translate extracellular cues into cellular responses by harnessing conformational changes, ion flux or enzymatic activity. Fast-acting ligand-gated ion channels regulate membrane potential on millisecond timescales, while G-protein-coupled receptors elicit second-messenger cascades over seconds to minutes. Enzyme-linked receptors activate intracellular kinases upon dimerisation, and nuclear hormone receptors modulate gene transcription over hours. Beyond signalling, membrane proteins control solute gradients, vesicular traffic and membrane remodelling, underpinning processes from water homeostasis to mechanotransduction. Dysregulation of these systems contributes to diverse pathologies, making membrane receptors and transporters prime drug targets across oncology, neurology and metabolic disease.

Research from Nature Portfolio

Haem-dependent dimerisation of a membrane-associated receptor component has been shown to drive cancer cell proliferation and chemoresistance. Crystallographic structures of the cytosolic domain reveal stable homodimers assembled via stacking of two protruding haem groups. Coordination of the haem iron by conserved tyrosine residues and an interfacial haem-haem interaction is essential for associations with receptor tyrosine kinases and cytochrome P450 enzymes. Disruption of haem binding, either by carbon-monoxide ligation or by haem depletion, prevents dimer formation, attenuates downstream signalling and restores drug sensitivity.

Members of the chloride intracellular channel (CLIC) family have been demonstrated to act as pH-triggered membrane fusogens. Purified CLIC5 directly interacts with lipid bilayers under acidic conditions, catalysing liposomal fusion as evidenced by both lipid and content mixing. Exposure of a hydrophobic inter-domain interface upon membrane association is crucial for fusogenic activity, and mutation of a conserved hydrophobic residue abrogates fusion in vitro and impairs developmental membrane remodelling in vivo, uncovering a physiological role in organellar dynamics.

Cryo-electron microscopy of full-length TRPV2 has revealed dual gating constrictions in the pore that distinguish it from vanilloid-sensitive relatives. Structures in the apo state display inherently wider upper and lower gates compared with TRPV1, and conformational features of peripheral helices suggest determinants of isoform-specific activation thresholds. These insights define structural correlates of TRPV2’s pharmacological profile and inform the design of selective modulators for mechanosensitive channelopathies.

Receptors and Membrane Biology publication trend

The graph below shows the total number of articles in receptors and membrane biology across all publications each year (not limited to Nature Index journals).

Technical terms

Ligand-gated ion channel: A multimeric membrane protein that opens a central pore for ion flux upon extracellular ligand binding, altering membrane potential.

G-protein-coupled receptor (GPCR): A seven-transmembrane receptor that activates heterotrimeric G-proteins to trigger intracellular second-messenger cascades.

Dimerisation: The assembly of two protein subunits, often driven by ligand or cofactor binding, to form a functional receptor complex.

Fusogen: A protein that promotes merging of lipid bilayers, facilitating membrane fusion and content mixing.

Ball-and-chain gating: A mechanism in which an intracellular peptide (‘ball’) occludes the channel pore from within, preventing ion conductance.

AMKP (AMP-activated protein kinase): A cellular energy sensor that inhibits anabolic processes and regulates transporter abundance under low-ATP conditions.

Allosteric modulator: A compound that binds to a receptor site distinct from the orthosteric ligand pocket, tuning receptor activity positively or negatively.

References

1. Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nature Communications (2016).
2. Chloride intracellular channel (CLIC) proteins function as fusogens. Nature Communications (2024).
3. Structure of the full-length TRPV2 channel by cryo-EM. Nature Communications (2016).
4. CryoEM structures of the human CLC-2 voltage-gated chloride channel reveal a ball-and-chain gating mechanism. eLife (2024).
5. Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin-2. JCI Insight (2024).
6. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Signal Transduction and Targeted Therapy (2023).