Trpv4 (rat, UniProt Q9ERZ8) - manual literature synthesis

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from the cached publications in publications/ and the UniProt record. Every claim carries
its source.

Identity

• Rat Trpv4 (RGD:69337, GeneID 66026), 871 aa, Swiss-Prot reviewed entry TRPV4_RAT.
• Member of the TRP superfamily, TRPV subfamily: six transmembrane helices with a pore
  loop between S5 and S6, an N-terminal ankyrin-repeat domain, cytoplasmic N- and C-termini
  PMID:11081638.
• Assembles as a homotetramer [UniProt Q9ERZ8 SUBUNIT "Homotetramer." (By similarity)].

Discovery and channel activity

• Cloned from rat kidney as VR-OAC (vanilloid receptor-related osmotically activated
  channel) PMID:11081638.
  The parallel mouse clone was named OTRPC4 PMID:11025659.
• Rat VR-OAC in CHO cells: a cation-selective channel gated by hypotonicity
  PMID:11081638;
  K+ permeability slightly above Na+, Cl- much lower; 310 pS single-channel conductance
  PMID:11081638.
• Ca2+ enters through the channel and triggers store release
  PMID:11081638.
• Not store-operated PMID:11081638.
• Responds to hypotonicity, not to low Na+ at constant osmolality
  PMID:11081638.
• Gating presumed via membrane stretch PMID:11081638.
• Temperature: rat VR-OAC did not respond to heat alone in isotonic medium in the original
  CHO assay, though osmosensitivity peaked at 37 C PMID:11081638. Mouse TRPV4 was later
  shown to be warm-activated in oocytes and HEK293 cells
  PMID:12151520.
  Rat diaphragmatic lymphatics use TRPV4 to sense temperature [PMID:32706268, abstract only].
• Pharmacology used in rat studies: agonists 4alpha-PDD and GSK1016790A; blockers
  HC-067047, GSK2193874, ruthenium red [PMID:22962011; PMID:23136043; PMID:32706268].

Localization

• Plasma membrane: eGFP-rat VR-OAC at the plasma membrane in CHO cells PMID:11081638;
  endogenous TRPV4 at the surface of rat aortic smooth muscle cells by immunostaining and
  surface biotinylation PMID:20650893;
  a biotinylatable plasma-membrane pool in rat astrocytes PMID:21262839.
• Overexpressed TRPV4-GFP in F11 cells is enriched in filopodia, lamellipodia, growth cones,
  membrane ruffles and cortical actin PMID:20657843.
• Apical membrane of epithelia, cilia, adherens junctions and ER (assembly) are recorded by
  UniProt by similarity to mouse and human.

Regulation and partners (rat data)

• AT1aR forms a constitutive complex with TRPV4; angiotensin recruits beta-arrestin 1, which
  acts as adaptor for the E3 ligase AIP4 (ITCH); TRPV4 is ubiquitinated and internalized,
  reducing 4alpha-PDD-evoked Ca2+ influx in rat vascular smooth muscle cells
  PMID:20650893.
• AQP4/TRPV4 complex in rat astrocytes; TRPV4 siRNA abolishes hypotonicity-induced Ca2+ rise
  and regulatory volume decrease (RVD)
  PMID:21262839.
• The TRPV4 C-terminus binds actin and tubulin directly and stabilizes microtubules in vitro;
  activation of TRPV4 disassembles microtubules, retracts growth cones and shortens neurites
  of IB4+ rat DRG neurons; a pull-down complex also contains PKCepsilon and CaMKII
  PMID:20657843.

Physiology (rat and orthologs)

• Pulmonary artery smooth muscle: 4alpha-PDD raises [Ca2+]i via TRPV4 coupled to RyR2;
  TRPV4 protein increases in chronic hypoxia [PMID:22962011, abstract only].
• Lung endothelium: TRPV4 blockade prevents the permeability increase and edema caused by
  high pulmonary venous pressure PMID:23136043.
• Lymphatic muscle: TRPV4 mediates temperature-dependent contraction frequency PMID:32706268.
• Systemic osmoregulation (mouse knockout): impaired drinking and ADH release after
  hyperosmotic challenge PMID:14581612.
• Adipocytes (mouse): TRPV4 represses Pgc1a/Ucp1 and promotes chemokine expression via
  ERK1/2; knockout mice resist diet-induced obesity and insulin resistance PMID:23021218.

Open questions

• Whether TRPV4 is directly stretch-gated or responds to swelling through accessory proteins
  (AQP4, actin cytoskeleton) and lipid messengers is not settled; PMID:21262839 argues that
  AQP4 is needed for TRPV4 to act as an astrocyte osmosensor.
• The rat channel's direct heat sensitivity is not resolved: there is a negative result in
  PMID:11081638, and the positive data come from mouse/human channels.