Prostaglandin F receptor (FP) is areceptor belonging to theprostaglandin (PG) group of receptors. FP binds to and mediates the biological actions ofprostaglandin F2α (PGF2α). It is encoded in humans by thePTGFRgene.[5]
ThePTGFR gene is located on human chromosome 1 at position p31.1 (i.e. 1p31.1), contains 7 exons, and codes for aG protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (seerhodopsin-like receptors#Subfamily A14).PTGFR is expressed as twoalternatively spliced transcript variants encoding differentisoforms, FPA and FPB, which have different C-terminal lengths.[5][6][7]MicroRNA miR-590-3p binds to theThree prime untranslated region of the FP gene to repress itstranslation. miR-590-3p thus appears to be a negative regulator of FP expression in various cell types.[8]
In humans, FPmRNA and/or protein is highly expressed in the uterine myometrium; throughout the eye (endothelium and smooth muscle cells of blood vessels of the iris), ciliary body and choroid plexus; ciliary muscle (circular muscle, collagenous connective tissues; sclera; and ovarian (follicles andcorpus luteum). Studies in mice indicate that FP mRNA and/or protein is expressed in diverse tissues including the kidney (distal tubules), uterus, and ovary (Luteal cells of corpus luteum.[9][10]
The FP receptor is the least selective of theprostenoid receptors in that it is responsive to PGD2 and to a lesser extent PGE2 at concentrations close to those of PGF2α. Standardprostanoids have the following relative efficacies asreceptor ligands in binding to and activating FP: PGF2α>PGD2>PGE2>PGI2=TXA2. In typical binding studies, PGF2α has one-half maximal binding and cell stimulating actions at ~1nanomolar whereas PGD2 and PGE2 are ~5- to 10-fold and 10-100-fold weaker than this. The synthetic analogs that like PGF2α act as selectivereceptor agonists of FP viz.,cloprostenol, flupostenol,latanoprost, andtafluprost (acid form) have FP binding affinities and stimulating potencies similar to PGF2α while others asenprostil,sulprostone,U46619, carbacyclin, andiloprost are considerably weaker FP agonists. Fluprostenol is a widely used clinically as a selective FP receptor agonist; latanoprost is a suitable substitute.[9]
Currently, there are no selectivereceptor antagonists for FP.[9]
FP is classified as a contractile type of prostenoid receptor based on its ability, upon activation, to contract certain smooth muscle preparations and smooth muscle-containing tissues such as those of the uterus. When bound to PGF2α or other of its agonists, FP mobilizes primarilyG proteins containing theGq alpha subunit bound to of the Gq-Gβγ complex(i.e. Gqβγ). Gqβγ then dissociate into its Gq and Gβγ components which act to regulate cell signaling pathways. In particular, Gq stimulatescell signal pathways involvinga)phospholipase C/IP3/cellCa2+ mobilization/diacylglycerol/protein kinase Cs;calmodulin-modulatedmyosin light chain kinase;RAF/MEK/Mitogen-activated protein kinases; PKC/Ca2+/Calcineurin/Nuclear factor of activated T-cells; and theEGF cellular receptor.[7][11] In certain cells, activation of FP also stimulatesG12/G13-Gβγ G proteins to activate theRho family of GTPases signaling proteins andGi-Gβγ G proteins to activateRaf/MEK/mitogen-activated kinase pathways.[11]
Studies using animals genetically engineered to lack FP and examining the actions of EP4 receptor agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. It has been regarded as the most successful therapeutic target among the 9 prostanoid receptors.[11]
Animal and human studies have found that the stimulation of FP receptors located onCiliary muscle andtrabecular meshwork cells of the eye widens the drainage channels (termed theuveoscleral pathway) that they form. This increases the outflow ofaqueous humor from theanterior chamber of the eye throughSchlemm's canal to outside of the eyeball. The increase in aqueous humor outflow triggered by FP receptor activation reducesIntraocular pressure and underlies the widespread usage of FPreceptor agonists to treatglaucoma.László Z. Bitó is credited with making critical studies to define this intraocular pressure-relieving pathway.[12] Three FP receptor agonists are approved for clinical use in the USA viz.,travoprost,latanoprost, andbimatoprost, and two additional agonists are prescribed in Europe and Asia viz.,unoprostone andtafluprost.[13]
Since FP receptors are expresses in humandermal papillae and the use of FP agonists to treat glaucoma has as a side-effect an increase in eyelash growth, it has been suggested that FP agonists may be useful for treating baldness. This is supported by studies in the stump-tailedMacaque primate model of androgen-induced scalpalopecia which have found that the FP agonist,latanoprost, promotes scalp hair growth. These studies have not yet been translated into baldness therapy in humans.[12]
FP receptor activation contributes to the regression of thecorpus luteum and thereby theestrous cycle in many species of farm animals. However, it does not make these contributions in mice and its contribution to these functions in humans is controversial. The receptor has been in use as a target for decades to regulate the estrous cycle as well as to induce labor in pregnant farm animals[14][15] FPgene knockout in female mice blocksparturition. That is, these FP-/- mice fail to enter labor even if induced byoxytocin due to a failure in copus luteum regression and consequential failure to stop secretingprogesterone (declining progesterone levels trigger labor).[14][15][16] Studies with monkey and human tissues allow that FP receptors may have a similar function in humans.[10]
One side effect of applying FP receptor agonists to eyelashes in humans is the development of hyperpigmentation at nearby skin sites. Follow-up studies of this side effect indicated than human skin pigment-formingmelanocyte cells express FP receptors and respond to FP receptor agonists by increasing theirdendricites (projections to other cells) as well as to increase theirtyrosinase activity. Since skin melanocytes use their dendrites to transfer the skin pigmentmelanin to skinkeratinocytes thereby darkening skin and since tyrosinase is the rate-limiting enzyme in the synthesis of melanin, these studies suggest that FP receptor activation may be a useful means to increase skin pigmentation.[17]
PGF2α triggers theNFATC2 pathway stimulating skeletal muscle cell growth.[18] PGF2α, shown or presumed to operate by activating FP receptors, has complex effects on boneosteoclasts andosteoblasts to regulatebone remodeling. However, further studies on the impact of the PGF2α-FP axis on bone are needed to better understand the pathophysiology underlying bone turnover and to identify this axis as a novel pharmacological target for the treatment of bone disorders and diseases.[12][19]
Unlike other prostaglandin receptors which have been shown in numerous studies to contribute to inflammatory and allergic responses in animal models, there are few studies on the function of FP receptors in these responses. Gene knockout studies in mice clearly show that FP mediates the late phase (thromboxane receptor mediates the early phase) of thetachycardia response to the pro-inflammatory agent,lipopolysaccharide.[16][20]PTGFR knockout mice also show a reduction in the development of pulmonary fibrosis normally caused by microbial invasion orbleomycin treatment. Finally, administration of PGF2α to mice causes an acute inflammatory response and elevated biosynthesis of PGF2α has been found in the tissues of patients withrheumatoid arthritis,psoriatic arthritis, and other forms of arthritis. While much further work is needed, these studies indicate that PGF2α-FP axis has some pro-inflammatory and anti-inflammatory effects in animals that may translate to humans.[7] The axis may likewise play role in human allergic responses: PGF2α causes airway constriction in normal and asthmatic humans and its presence in human sputum is related to sputum eosinophil levels.[21]
PGF2α simulates an increase insystolic blood pressure inwild type but not FP(−/−) mice. Furthermore, FP(-/-) mice have significantly lower blood pressure, lower plasmarenin levels, and lower plasmaangiotensin-1 levels than wild-type mice, and FP agonists have a negativeinotropic effect to weaken the strength of heart beating in rats. Finally, FP(−/−) mice deficient in theLDL receptor exhibit significantly less atherosclerosis than FP(+/+) LDL receptor-deficient mice. Activation of FP thus has pathophysiological consequences for the cardiovascular system relative to blood pressure, cardiac function, and atherosclerosis in animal models. The mechanism behind these FP effects and their relevancy to humans have not been elucidated.[12]
FP receptor agonists, specifically latanoprost, travoprost, bimatoprost, and tafluprost, are currently used as first-line drugs to treat glaucoma and other causes of intra-ocular hypertension (seeGlaucoma#Medication).[22]
The FP receptor agonist,bimatoprost, in the form of an 0.03% ophthalmic solution termedLatisse, is approved by the USFood and Drug Administration to treathypotrichosis of the eyelashes, in particular to darken and lengthen eyelashes for cosmetic purposes. Eyelid hypotrichosis caused by[17]
FP receptor agonists are used as highly effective agents to synchronize the oestrus cycles of farm animals and thereby to facilitate animal husbandry.[23]
Eyelash hypotrichosis due to the autoimmune diseasealopecia areata, or to chemotherapy, have been successfully treated with FP agonists in smalltranslational research studies. In a randomized, double-blind, placebo-controlled pilot study of 16 men withmale pattern baldness (also termed androgenetic alopecia) topical application of the FP agonist, latanoprost, for 24 weeks produced a significant increase in scalp hair density. Despite these findings, however, a case report of one woman with femalepattern hair loss found that injection of FP agonist bimatoprost failed to influence hair growth.[17]
In preliminary studies, three Korean patients with periorbitalvitiligo (i.e. skin blanching) were treated topically with the FP receptor agonist, latanoprost, for two months; the three patients experienced 20%, 50%, and >90% re-pigmentation of their vitiligo lesions. Fourteen patients with hypopigmented in their scarreed tissues were treated with the FP receptor agonist,bimatoprost, applied topically plus laser therapy and topicaltretinoin orpimecrolimus. Most patients demonstrated significant improvement in their hypopigmentation, but the isolated effect of topical bimatoprost was not evaluated. These studies allow that FP receptor agonists may be useful for treating hypopigmentation such as occurs in scar tissue as well as diseases like vitiligo,tinea versicolor, andpityriasis alba.[17]
Thesingle-nucleotide polymorphism (SNP) A/G variant, rs12731181, located in theThree prime untranslated region ofPTGFR has been associated with increased risk for hypertension in individuals from southern Germany; while this association was not replicated in other European populations, it was found in a Korean population. This SNP variant reduces the binging ofMicroRNA miR-590-3p toPTGFR; since this binding repressestranslation of this gene, the rs127231181 variant acts to increase expression of the FP receptor.[8]PTGFR SNP variants rs6686438 and rs10786455s were associated with positive and SNP variants rs3753380, rs6672484, and rs11578155 inPTGFR were associated with negative responses to latanoprost for the treatment of Open-Angle Glaucoma in a Spanish population.[24]PTGFR SNP variants rs3753380 and rs3766355 were associated with a reduce response to latanoprost in a Chinese population study.[25]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
