Oxytocin & Prostaglandins

Oxytocin Signal Transduction Mechanism

1. Oxytocin binds a G-protein coupled receptor (Gq). 2. Gq-PCR then activates phospholipase C, which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 3-phosphate (IP3) and diacylglycerol (DAG). 3. IP3 causes the *release of stored calcium and movement of calcium into cells*. 4. Calcium combines with calmodulin to *activate myosin light chain kinase (MLCK)*. 5. Calcium and MLCK act together to *stimulate smooth muscle contraction in the uterine wall and myoepithelium of the mammary gland*. In addition, protein kinase C (PKC) activation and other actions of the oxytocin receptor *increase synthesis of prostaglandins E2 and F2alpha, which also increases uterine smooth muscle contraction*. During parturition, PGE2 and PGF2a positively feedback on the posterior pituitary stimulating it to release more oxytocin. The increased release of estrogen at the end of pregnancy may serve to induce the synthesis of oxytocin receptors in the uterine wall.

Oxytocin & ADH

ADH = Antidiuretic Hormone = Vasopressin Both oxytocin and ADH are released from the neuroendocrine cells extending into the posterior pituitary and are thus similar in structure. However, *they differ at two positions and thus bind different receptors and ellicit very different functions.*

Prostaglandin E2 Receptor Binding & MOA

PGE2 binds to 3 distinct receptors EP1, EP2, and EP3. EP2 levels are HIGH during pregnancy = maintains the uterine smooth muscle in a relaxed state. In addition, EP2 receptors are present on vascular smooth muscle, gastric smooth muscle, and bronchioles where they promote relaxation. EP1 & EP3 increase at the end of pregnancy = promotes contraction of the uterus.

Prostaglandin F2alpha Receptor Binding & MOA

PGF2alpha binds to the FP receptor, which *promotes uterine smooth muscle contraction.*

Regulation of Oxytocin

Short-Term Regulation - Physiological - Psychological - Oxytocin is rapidly synthesized & degraded Long-Term Regulation - Synthesis of oxytocin and oxytocin receptor - *Promoted by estrogen* - Cholesterol enhances affinity of oxytocin receptor for oxytocin - *Inhibited by progesterone*

Prostaglandin Levels During Pregnancy

During pregnancy, EP1 and EP3 are LOW and EP2 is HIGH. Hence *PGE2 causes the uterus to RELAX.* When labor starts, EP1 and EP3 are HIGH and EP2 is LOW. Hence, decreased PGE2 causes the uterus to CONTRACT.

What are the behavioral effects of oxytocin?

In addition to the oxytocin released by the posterior pituitary into the bloodstream, there is also oxytocin released from oxytocin releasing neurons in the brain that project into various brain regions and ellicit the behavioral effects associated with oxytocin.

Stages of Lactation

Mammogenesis: growth of mammary glands and breast tissue - *Induced by Estrogen & Progesterone* Lactogenesis: production of milk. - *Induced by Prolactin* Milk Ejection: movement of milk out of the breast. - *Induced by Oxytocin*

Behaviorial Effects of Oxytocin

Mediated by *oxytocin releasing neurons in the brain*, NOT the H-P axis! 1. Sexual arousal 2. Memory 3. Social Bonding 4. Empathy 5. Increased feelings of trust, compassion, and empathy especially towards one's own social group. 6. Increases distrust of outsiders, may promote ethnocentric behavior.

What hormonal changes during pregnancy promote oxytocin's action during parturition?

At the end of a pregnancy, there is a *reduction in progesterone coupled with the increase in estrogen* that promotes oxytocin's synthesis and action during parturition.

Oxytocin as the "Facilitator of Life"

Birth: Ejection of newborn. Infancy: Milk let-down Childhood: Mother-child bonding Adolescence: Social interactions, feeling of well-being Adulthood: Trust within the group, bonding with mate, distrust of outsiders and rivals Reproduction: Sexual arousal and performance

Oxytocin & Sexual Intercourse

Oxytocin causes contraction of the uterus in women and, in men, of the prostate and myoid cells of the seminiferous tubule. Promotes and facilitates reproduction.

Oxytocin Structure

Oxytocin is a nonapeptide (9 amino acids). It has an amide at the C-terminal end (red) and a disulfide bond connecting the two cysteines (blue).

What is the role of oxytocin in parturition and lactation?

Oxytocin is released from the neuroendocrine axons of the posterior pituitary into the blood stream where it will interact with mammary glands, the uterus, and the placenta. Oxytocin causes: - Increased uterine contractions - Increased placental production of prostaglandins - Milk let down and delivery of milk for lactation. (Does NOT make the milk - prolactin does that! Just stimulates the let down of already made milk.)

Oxytocins Role in Parturition

Oxytocin is released from the posterior pituitary and causes: - Increased uterine contractions - Increased placental production of prostaglandins

Oxytocins Role in Lactation

Oxytocin is released from the posterior pituitary and causes: - Milk let down and delivery of milk for lactation. (Does NOT make the milk - prolactin does that! Just stimulates the let down of already made milk.)