🌊 1. Introduction — Beyond Kidney Pipes

Aquaporins (AQPs) are protein “water pipes” in cell membranes. They let water zip through lipid barriers — key for maintaining body water balance. In the kidney, AQP1–AQP4 work together to reabsorb water:

• AQP1: in proximal tubule & descending limb — does baseline reabsorption.
• AQP2: in collecting duct; controlled by vasopressin (AVP) → phosphorylates AQP2 → inserts into membrane → more water reabsorbed.
• AQP3 & AQP4: on basolateral side to let water exit the cell.

Mutations in AQP2 or AVPR2 cause nephrogenic diabetes insipidus (can’t concentrate urine). But AQPs aren’t just kidney tools — they exist across tissues, affecting many processes!

🧬 2. Structure — The Molecular Plumbing Design

There are 13 mammalian AQPs (AQP0–AQP12), grouped into:

1. Orthodox AQPs: Only water (AQP0, 1, 2, 4, 5, 6, 8)
2. Aquaglyceroporins: Water + glycerol (AQP3, 7, 9, 10)
3. Superaquaporins: AQP11–12 — intracellular, in ER, low similarity (~20%).

🧩 Structure highlights:

• 6 transmembrane helices + 2 half-helices (loops B & E) with the NPA motif (Asn-Pro-Ala).
• Four monomers assemble → tetramer with a central pore (for gases/ions).
• The ar/R region acts as a selectivity filter — narrower in orthodox, wider in glycerol channels.
• Post-translational tweaks (phosphorylation, ubiquitination) fine-tune each AQP’s activity.

⚗️ 3. Transport of Non-Water Solutes

AQPs are multitaskers — many also pass small molecules:

• Glycerol (via AQP3, 7, 9, 10): vital in fat and liver metabolism → link to obesity & diabetes.
• H₂O₂ (peroxiporins): act in redox signaling and stress response.
• Gases (CO₂, O₂, NH₃, NO): for respiration and pH balance.
• Ions: AQP6 can conduct anions at low pH; AQP1 passes cations when activated by cGMP.
• Metalloids: orthosilicic acid (Si), boric acid (B), arsenic (AsIII) pass through aquaglyceroporins.

Fun fact: AQP1-null red blood cells move CO₂ 60 % slower — proving AQPs move gases too!

🧫 4. AQPs and Cell Migration — Water-Powered Movers

Cells crawl! AQPs help them by shaping cell edges:

• Filopodia & lamellipodia need rapid local swelling → AQP-mediated water influx creates space for actin to grow.
• AQP9 activates Cdc42 to form filopodia.
• AQP1 & AQP5 help lamellipodia extend → faster movement.
• AQP2 interacts with β1-integrin to remodel focal adhesions during kidney development.
• AQP3 and AQP5 also influence secretion of matrix metalloproteinases (MMPs) that digest extracellular matrix.

🌀 “Osmotic engine model”: in confined spaces, AQPs + ion exchangers drive migration by controlling cell volume changes.

🧷 5. AQPs and Cellular Adhesion

Cells must stick together or detach at the right times.

• AQP0 (in lens): doubles as a junction protein forming tight “square arrays” between fiber cells — crucial for lens transparency 👁️.
• AQP4-M23 forms orthogonal arrays of particles in brain — possibly aids adhesion (still debated).
• AQP3 & AQP5 regulate E-cadherin, β-catenin, ZO-1, etc., affecting epithelial tightness.
  • AQP3 ↑ adhesion;
  • AQP1/5 ↓ adhesion → more migration potential.
• Their C-terminal tails and protein partners (like ezrin, β-catenin) drive these effects.

🧭 6. AQPs and Cell Polarity

Epithelial cells need clear “top vs. bottom” organization.

• Overexpression of AQP5 in MDCK or breast cancer cells destroys polarity → cells become disorganized and invasive.
• AQP5 inversely correlates with Scribble, a polarity protein — loss of polarity = early cancer hallmark. So AQPs can help maintain or break down epithelial order.

🔔 7. AQPs and Cellular Signalling

AQPs don’t just transport — they signal too!

🔹 Intracellular (inside the cell)

• H₂O₂ transport via peroxiporins (AQP1, 3, 5, 8, 9, 11) regulates:
  • NF-κB, TNF, and redox signaling
  • T cell migration (AQP3-dependent)
  • Heart hypertrophy (AQP1 role in ROS signalling) → AQPs = gatekeepers of oxidative messages.

🔹 Transport-independent signalling

• AQP5 can activate RAS-ERK pathways via phosphorylation at Ser156 → triggers c-Src interaction → enhances proliferation & migration.
• AQPs also influence β-catenin/WNT pathways via junction proteins.

🔹 Intercellular (between cells)

• AQPs are found in extracellular vesicles (EVs) — little “packages” of communication.
  • AQP4-M1 EVs make glioma cells more invasive, AQP4-M23 EVs cause apoptosis.
  • AQP1 adds deformability to EVs so they can squeeze through ECM.

🧩 8. AQPs and Protein–Protein Interactions

Each AQP interacts with a set of partners regulating its location or signaling:

• AQP2–SPA-1 (PDZ domain) controls kidney trafficking.
• AQP4–α-syntrophin localizes it in muscles.
• AQP5–Scribble affects migration and polarity.
• AQP0–calmodulin gates water flow in the lens (regulated by Ca²⁺ and phosphorylation).
• AQP5–c-Src activates RAS signalling. These interactions create “AQP networks” fine-tuned by phosphorylation and ubiquitination.

🎗️ 9. AQPs and Cancer

🧬 Development & Spread

In many adenocarcinomas (breast, colon, pancreas, lung):

• AQP1 & AQP5 overexpression → higher invasiveness, lymph-node metastasis, poorer prognosis.
• AQP5 often relocates inside the cell, meaning its signalling role (RAS activation) is key.
• AQPs influence epithelial–mesenchymal transition, MMP secretion, and angiogenesis.

💊 Drug Resistance & Therapy

• Silencing AQP5 ↑ apoptosis and sensitivity to doxorubicin / 5-FU.
• Overexpressing AQPs can either increase or decrease chemosensitivity — depends on context.
• Peroxiporins (AQP3/9) make cells more sensitive to pharmacologic ascorbate (vitamin C) that generates H₂O₂.
• AQP1–β-catenin interaction predicts good response to anthracyclines in breast cancer.

Thus, AQPs may become prognostic markers or drug targets 🎯.

🧠 10. Conclusions — More Than Water Channels

Aquaporins:

• Do much more than water transport.
• Affect migration, adhesion, polarity, signalling, and cancer progression.
• Act through solute movement and protein interactions.
• Could become biomarkers and therapy targets. Future research will need to map the entire “AQP interactome” and how these proteins coordinate within cells.

🧭 Quick Recap Mnemonic

“MAPS-SIC” — AQPs influence: Migration, Adhesion, Polarity, Signalling, Solute transport, Ion/gas flow, Cancer spread.