There are various splicing forms. Canonical form transcript (hg38), including UTRs: chr12:30,911,694 - 30,925,516, size: 13,823bp on forward (+) strand; coding region: chr12: 49,950,746-49,958,881 size: 8,136bp, according to UCSC. Four exons: exon1 (nt 1 - 450) codes for amino acids (aa) 1-120, exon2 (nt 3415 - 3579) for aa 121-175; exon3 (nt 3890 - 3970) for aa 176-202, and exon4 (nt 4659 - 8141) for aa 203-271 (nextProt).

Aquaporins are a family of hydrophobic transmembrane channel proteins involved in transport of water and small molecules in response to osmotic gradients. They are distributed throughout many tissues, with various known roles of production, secretion, reabsorption and regulation of water, but also of cell migration (angiogenesis), signal transduction, and cell proliferation. There are 14 AQPs in humans (and 5 pseudogenes): MIP (previously called AQP0), AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8, AQP9, AQP10, AQP11, AQP12Aand AQP12B. They are classified into two families: orthodox aquaporins, that transport water only, and aquaglyceroporins (AQP3, AQP7 and AQP9), which also transport glycerol, urea and other small molecules. AQPs form homo-tetramers (Review in Papadopoulos and Saadoun, 2015). The monomeric units of AQPs are ~30 kDa proteins and consist of 6 transmembrane α-helices (M1, M2, M4 to M6 and M8), 2 intramembrane half helices (M3 and M7), and 5 connecting loops (loops A to E) (Review in Verkman et al., 2014). They bear conserved intramembrane Asn-Pro-Ala (NPA) sequence motifs in the intramembrane domains, and six tilted transmembrane helices per monomer, with linkers (loops A to E). The NPA motifs act as hydrogen-bond donors and acceptors that coordinate the transport of water through the pore (Verkman et al., 2014).

Aquaporin-2 canonical form: 271 aa; 28.837kDa; other isoforms; 223, and 244 aa. AQP2 is a transmembrane protein, with a N-term and a C-term cytoplasmic domains: amino acids 1 - 16 (Cytoplasmic), 17 - 34 (Transmembrane), 35 - 40 (Extracellular ("Loop A")), 41 - 59 (Transmembrane), 60 - 85 (Cytoplasmic ("Loop B")), 86 - 107 (Transmembrane), 108 - 127 (Extracellular ("Loop C")), 128 - 148 (Transmembrane), 149 - 156 (Cytoplasmic ("Loop D")), 157 - 176 (Transmembrane), 177 - 202 (Extracellular ("Loop E")), 203 - 224 (Transmembrane), 225 - 271 (Cytoplasmic) (Figure. 1).

Helical subunits in Loop B and E juxtapose to form a water pore in the monomere. The central pore of the homotetramer (Figure. 2) would be a path for ion and gas (Review in Huber et al., 2012). Remarkable sites: (Figure. 1)
NPA: aa 68-70, 184-186
N-myristoylation sites (role in membrane targeting): aa 27-32, 29-34, 49-54, 78-83, 96-101, 128-133, 175-180, 211-216.
N-glycosylation sites: aa 123-126.
Protein kinase C phosphorylation sites: aa 195-197, 231-233 (Thr 195 and Ser 231); Casein kinase II phosphorylation site: aa 108-111 (Thr 108), 148-151 (Ser 148), 229-232 (Ser 229), 244-247 (Thr 244); cAMP-and cGMP-dependent protein kinase (PKA) phosphorylation site :aa 253-256.
Cell attachment sequence RGD (plays a role in cell adhesion): aa 113-115.
Microbodies C-terminal targeting signal (targeting to organelles such as peroxisomes): aa 269-271.

AQPs are widely expressed. AQP2 is mainly expressed in the kidney. Renal collecting duct principal cells
Extra-renal localizations: Ear, epididymis, vas deferens, vagina. Both AQP1 and AQP2 are expressed in the endometrium. AQP2 endometrial expression is menstrual cycle-dependent (high at the proliferative and midsecretory phases).

AQP2 undergoes a constitutive recycling: its trafficking from intracellular vesicles into the plasma membrane and endocytic retrieval to its intracellular storage site. AQP2 forms homotetramers in the endoplasmic reticulum, passes through the Golgi apparatus and is stored in intracellular vesicles in the perinuclear region. Under resting conditions, AQP2 binds monomeric G-actin (ACTG1). F-actin destabilization facilitates translocation of AQP2 to the apical plasma membrane and water reabsorption (Vukićević et al., 2016).

AQPs mains role is to maintain tissue water balance. AQPs also facilitate cell migration, cell proliferation and cell adhesion. Cell migration: AQPs concentrate at the leading end of migrating cells and facilitate the formation of the lamellipodium (Papadopoulos and Saadoun, 2015). Cell proliferation: AQPs may activate transduction pathways such as the mitogen-activated protein kinase pathways or the Wnt/beta-catenin ( CTNNB1) signaling.
AQP2 key physiological role is water reabsorption in collecting duct of the kidney to concentrate urine.
Vasopressin / vasopressin receptor / aquaporin-2 axis
In the kidney, AVP 46535 (vasopressin) binds to AVPR2 732 (type 2 vasopressin receptor (V2R)) located in the basolateral membrane of the principal cells of the collecting ducts and increases osmotic water transport through the regulation of the aquaporin-2 water channel localized in the kidney connecting tubules and collecting ducts. Upon binding of vasopressin to AVPR2, the cAMP/PKA (PRKAR1A 387) signal is activated, PRKAR1A is recruited to the vesicles through PRKAR1A-anchoring proteins (AKAPs) (AKAP7 46846 co-localizes with AQP2) and results in phosphorylation in the C-terminus of AQP2 at serines 256, 264, and 269, withdrawing it from F-actin. AQP2 is subsequently translocated to the apical plasma membrane, and the water luminal permeability to increase water reabsorption from urine. Vasopressin also triggers increases in intracellular calcium required for AQP2 trafficking (Reviews in Jung and Kwon 2016; Ando and Uchida 2018; De Ieso and Yool 2018; Ranieri et al., 2019).
However, cAMP-independent mechanisms for AQP2 trafficking also exist.
Nuclear receptors, especially PPARG (Peroxisome proliferator-activated receptor gamma), NR1H2 (LXRB, Liver X receptor beta), NR1H4 (FXR, Farnesoid X receptor), NR3C1 (GR, Glucocorticoid receptor), NR3C2 (MR, Mineralocorticoid receptor) and ESR1 (Estrogen receptor alpha) regulate AQP2 abundance and membrane translocation. PPARG induces increased AQP2 expression, sodium and water retention and edema. NR3C1 and NR1H4 also activate AQP2 expression. NR3C2 and NR1H2 reduce AQP2 expression. ESR1 mediates the inhibitory effect of estradiol on AQP2 expression (Zhang et al., 2016).
Other factors capable of regulating AQP2: extracellular osmotic pressure, insulin ( INS), nuclear factor kB (NFkB), renin/angiotensin/aldosterone system, kinins, nitric oxide, adenosine, ATP and endothelins. PTGER2 (Prostaglandin E receptor 2) also controls AQP2 expression. The phosphorylated activation of CREBBP upregulates AQP2 gene transcription (reviewed in Zhang et al., 2016).
Actin-polymerization/depolymerization
Actin-depolymerization promotes AQP2 trafficking to the plasma membrane. TPM3 and MSN (Tropomyosin 3 and Moesin) result in F-actin destabilization. MLCK (Myosin light chain kinase) also facilitates AQP2 trafficking to the plasma membrane by regulating actin filament organization.
RHOA stimulates actin polymerization, which inhibits AQP2 trafficking to the plasma membrane.
Transcription
FOSB (FosB proto-oncogene, AP-1 transcription factor subunit), CREBBP, calcineurins (protein phosphatase 3 subunits) MAPK3 / MAPK1 (so called "ERK1/ERK2") and NFAT5 (nuclear factor of activated T cells 5) increase AQP2 transcription, while NFkB reduces AQP2 gene transcription.
Endocytosis/ubiquitination/degradation
FOSB/ TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) (AP1/AP2) mediates clathrin-mediated endocytosis of AQP2. VTA1 (vesicle trafficking 1) facilitates AQP2 lysosomal degradation. MAPK14 (p38-MAPK) phosphorylates AQP2 to induce ubiquitination and proteasomal degradation of AQP2. Protein kinases C induce ubiquitination, endocytosis and degradation of AQP2 (Review in Vukićević et al., 2016).

AQP2 is responsible for nephrogenic non-X-linked diabetes insipidus, a disease characterized by the kidneys inability to concentrate urine (see below).