The oxytocin receptor system: structure, function, and regulation

Intracerebroventricular infusion of oxytocin during a six hour cohabitation period with a male is able to induce a partner preference in unmated female prairie voles.

“Intracerebroventricular infusion of OT during a six hour cohabitation period with a male is able to induce a partner preference in unmated female prairie voles [52].”

Oxytocin affects the cardiovascular system, including improving vasculature, possibly through interaction with sex hormones.

“and effects on the cardiovascular system in that it has been found to improve the vasculature, possibly in interaction with sex hormones (Gimpl and Fahrenholz 2001)”

The mPFC, cingulate, and insula express OT receptors.

“The mPFC, cingulate, and insula express OT receptors (Gimpl and Fahrenholz, 2001; Macdonald and Macdonald, 2010; Boccia et al., 2013)”

With sustained stimulation, oxytocin receptors can undergo desensitization and internalization, leading to physiological tolerance.

“With sustained stimulation OT receptors can undergo desensitization and internalization (18) leading to physiological tolerance.”

High-dose OT might saturate OT receptors and subsequently bind to vasopressin receptors, to which OT also has binding affinity and which can cause differing and sometimes opposite behavioral effects.

“In other words, high dose OT might saturate OT receptors and subsequently bind to vasopressin receptors, to which OT also has binding affinity and which can cause differing and sometimes opposite behavioral effects (18,38,76,77).”

Gonadal steroids regulate Oxt activity, and estrogen seems to have higher impact on the Oxt system.

“Gonadal steroids regulate Oxt activity, and among them, estrogen seems to have higher impact on the Oxt system (Richard and Zingg, 1990; Miller and Caldwell, 2015; Gimpl and Fahrenholz, 2001).”

OT facilitates OTR coupling to several different G-proteins and β-arrestins.

“OT facilitates OTR coupling to several different G-proteins and β-arrestins, allowing for multiple degrees of freedom for effects on neural activity (36, 37).”

The oxytocin receptor is under tremendous control by various regulatory elements that provide potential for asymmetric expression.

“The potential mechanisms for this surprising lateralization of both protein and transcript levels is unclear, but the oxytocin receptor is under tremendous control by various regulatory elements that provide potential for asymmetric expression (Gimpl and Fahrenholz, 2001).”

The ring portion of OT interacts with the first extracellular loop of OTR, while the 3-residue tail structure interacts with the extracellular N-terminal domain.

“The ring portion of OT interacts with the first extracellular loop of OTR, while the 3-residue tail structure interacts with the extracellular N-terminal domain (Gimpl and Fahrenholz, 2001; Zingg and Laporte, 2003).”

AVP ligand binding to V1aR activates two potential signaling cascades via Gq and Gi/o proteins, which can open nonspecific cationic channels or close K+ channels.

“AVP ligand binding to V1aR activates two potential signaling cascades via Gq and Gi/o proteins, which can open nonspecific cationic channels or close K+ channels (reviewed in Caldwell et al., 2008; Gimpl and Fahrenholz, 2001).”

OT ligand binding to OTR activates multiple G proteins that can exert diverse effects on cell function, including stimulation of cAMP (Gs), inhibition of adenylyl cyclase (Gi/o), stimulation of potassium channel currents (Gi) and activation of phospholipase C (Gq).

“OT ligand binding to OTR activates multiple G proteins that can exert diverse effects on cell function, including stimulation of cAMP (Gs), inhibition of adenylyl cyclase (Gi/o), stimulation of potassium channel currents (Gi) and activation of phospholipase C (Gq).”

Saimiri, a Pro8-OT species, has a substitution at F103Y, a key residue of the putative binding pocket of OTR.

“One important exception is in Saimiri. This Pro8-OT species has a substitution at F103Y, which is a key residue of the putative binding pocket of OTR (Gimpl and Fahrenholz, 2001; Vargas-Pinilla et al., 2015).”

Many amino acid substitutions in the OT receptors of New World monkeys are found in the N-terminus, the putative binding region for the C-tail of the OT ligand.

“Many of the amino acid substitutions in the OT receptors of NWM are found in the N-terminus the putative binding region for the C-tail of the OT ligand (Gimpl and Fahrenholz, 2001).”

Experimental substitutions of critical receptor residues typically result in a receptor that does not bind or signal.

“This is not unexpected, because experimental substitutions of these residues typically result in a receptor that does not bind or signal (Gimpl and Fahrenholz, 2001).”

A host of evidence reveals significant OT and V1aR crosstalk in other model species.

“A host of evidence reveals significant OT and V1aR crosstalk in other model species, including pharmacological studies (Gimpl and Fahrenholz, 2001; Gruber et al., 2012), physiological studies (Chini et al., 1996; Meyer-Lindenberg et al., 2011), and neuropeptide binding and behavioral changes (Loyens et al., 2012; Schorscher-Petcu et al., 2010; Song et al., 2014).”

The affinity of oxytocin binding to the oxytocin receptor has often been estimated to be KD ~100 nM, although a high affinity form with KD ~1 nM has also been reported.

“The affinity of oxytocin binding to the oxytocin receptor has often been estimated to be KD ~100 nM, although a high affinity form with KD ~1 nM has also been reported60.”

Intranasally administered oxytocin acts through the oxytocin receptor (OXTR).

“Intranasally administered oxytocin is considered to act through the oxytocin receptor (OXTR).21, 22”

OT receptors are expressed throughout brainstem nuclei implicated in the regulation of the ANS.

“and OT receptors are expressed throughout brainstem nuclei implicated in the regulation of the ANS (Gimpl & Fahrenholz, 2001).”

Gonadal steroids play a significant role in regulating oxytocin activity.

“It is well established that gonadal steroids play a significant role in regulating Oxt activity (68–71).”

Androgens and progesterone modulate oxytocin and oxytocin receptor expression, while estrogens seem to have the greatest impact on the oxytocin system.

“While androgens and progesterone modulate Oxt and Oxtr expression (72–75), it is the estrogens that seem to have the greatest impact on the Oxt system (68, 70, 74, 76–78).”

Oxytocin or the oxytocin receptor is expressed in some of the brain regions affected by developmental oxytocin exposure, though their expression often varies depending on species, age, and sex.

“Oxt or the Oxtr is expressed in some of these regions (68, 91), though their expression in these brain areas often varies depending on species, age, and sex.”

In animal and human studies, high OT plasma levels have also been associated with negative emotions involving anxiety and depression.

“in animal and human studies, high OT plasma levels have also been associated with negative emotions involving anxiety and depression.”

In rats, forced swimming and shaker stress increase plasma OT levels.

“In rats, forced swimming and shaker stress increase plasma OT levels (Gimpl & Fahrenholz, 2001).”

The OT receptor gene (OXTR) is located on chromosome 3p25, spans 17 kb, and encodes a 389 aa polypeptide with seven transmembrane domains belonging to the class I G-protein-coupled receptor family.

“The OT receptor gene (OXTR) is located on chromosome 3p25, spans 17 kb (Inoue et al., 1994), and encodes a 389 aa polypeptide with seven transmembrane domains belonging to the class I G-protein-coupled receptor family (Gimpl and Fahrenholz, 2001).”