Endocrinology/Objectives/Lecture 11

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Contents 1 Posterior pituitary 1.1 DESCRIBE the anatomical components of the hypothalamo-neurohypophyseal system. 1.2 UNDERSTAND the relationship between peptide hormones and their protein precursors. 1.3 DESCRIBE the stages of neurosecretion that occur after the arrival of the neurosecretory granule in the nerve terminal. 1.4 DEFINE stimulus-secretion coupling. 1.5 DEFINE stimulus-secretion-transcription coupling. 1.6 DESCRIBE the two principal physiological actions of vasopressin. 1.7 UNDERSTAND the capabilities of magnocellular neurons to integrate afferent information. 1.8 DEFINE an osmoreceptor. 1.9 DESCRIBE the relationship between osmoreceptive areas of the hypothalamus and magnocellular vasopressin neurons. 1.10 DESCRIBE the relationship between baroreceptive areas of the cardiovascular system and magnocellular vasopressin neurons. 1.11 DESCRIBE the two principal physiological sites of action of oxytocin. 1.12 UNDERSTAND the anatomy of the suckling reflex arc and the contributing role of oxytocin in this system. 1.13 REVIEW the role of prolactin in lactation. 1.14 DESCRIBE the actions of oxytocin on uterine smooth muscle. 1.15 DESCRIBE the contributing roles for oxytocin and the oxytocin receptor in the generation of uterine contractions at term. 1.16 DESCRIBE the secretory stimulus for oxytocin at parturition. 1.17 DISCUSS the similarities and differences in the signal transduction schemes regulating actions of oxytocin in mammary myoepithelium and uterine myometrium.

Posterior pituitary

DESCRIBE the anatomical components of the hypothalamo-neurohypophyseal system.

This system is composed of magnocellular neurons projecting from the supraoptic and paraventricular nuclei of the hypothalamus and into the posterior lobe of the pituitary (neurohypophysis).

These nuclei receive inputs from hypothalamic osmoreceptors such as those in the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT).

UNDERSTAND the relationship between peptide hormones and their protein precursors.

Peptide hormones, such as oxytocin and vasopressin (but also including ACTH, MSH, and others), are synthesized as protein precursors in the form of pre-prohormones.

Arginine vasopressin (AVP) is synthesized as pre-proarginine vasopressin/neurophysin II, which is composed of four segments:

1. Signal peptide
2. Arginine vasopressin
3. Neurophysin II
4. Glycoprotein

Oxytocin is synthesized as pre-prooxytocin/neurophysin I, which is composed of three segments:

1. Signal peptide
2. Oxytocin
3. Neurophysin I

The pre-propeptides are cleaved within vesicles during axonal transport to form AVP and oxytocin.

DESCRIBE the stages of neurosecretion that occur after the arrival of the neurosecretory granule in the nerve terminal.

• Exocytosis of neurosecretory granules
• Reuse of granule membrane by vesiculation produces coated caveolae
• Caveolae pinch off to form microvesicles
• Microvesicles shed coat fragments
• Partially coated microvesicles form
• Smooth microvesicles form
• Smooth microvesicles incorporated into lysosomal bodies

Newly synthesized granules are preferentially exocytosed, representing a readily releasable pool (10% of posterior pituitary contents). Old granules become Herring bodies.

DEFINE stimulus-secretion coupling.

Stimulus-secretion coupling is the process by which a stimulus causes the secretion of granules from the posterior pituitary. Arrival of an action potential constitutes the stimulus, which triggers the influx of sodium and subsequent depolarization of the nerve terminal. Depolarization opens voltage-gated calcium channels, which trigger the exocytosis of granule contents (e.g. oxytocin/neurophysin I).

DEFINE stimulus-secretion-transcription coupling.

Stimulus-secretion-transcription coupling is the process by which transcription activity of a gene is coupled to and regulated by the secretory activity of a neuron.

DESCRIBE the two principal physiological actions of vasopressin.

AVP's actions are essentially ways to balance body water:

• AVP binds V₂ receptors in the collecting ducts to inhibit water loss in the urine (diuresis).
• AVP also acts peripherally on V_1a receptors to stimulate vasoconstriction.
• AVP also stimulates thirst.

UNDERSTAND the capabilities of magnocellular neurons to integrate afferent information.

Magnocellular neurons receive and integrate inputs from several sources.

DEFINE an osmoreceptor.

Osmoreceptors are receptors in the OVLT and SVO that detect and respond to changes in plasma osmolarity.

DESCRIBE the relationship between osmoreceptive areas of the hypothalamus and magnocellular vasopressin neurons.

Osmoreceptors in the anterior hypothalamus (OVLT and SFO) send projections indirectly to AVP cell bodies in the SON and PVN to regulate vasopressin secretion.

DESCRIBE the relationship between baroreceptive areas of the cardiovascular system and magnocellular vasopressin neurons.

Baroreceptors in the carotid sinus, aortic arch, and left atrium send projections via the nucleus of the tractus solitarius to influence vasopressin secretion.

DESCRIBE the two principal physiological sites of action of oxytocin.

Oxytocin acts on mammary glands to stimulate myoepithelial cell contractions and milk letdown. It also acts on the myometrium to stimulate prostaglandin synthesis and uterine contractions to facilitate parturition.

UNDERSTAND the anatomy of the suckling reflex arc and the contributing role of oxytocin in this system.

Suckling initiates a spinal reflex that send cholinergic inputs to the paraventricular nucleus, causing exocytosis of neurosecretory granules. The secretory products are neurophysin I-bound oxytocin, a complex which readily dissociates in the higher pH of blood. Oxytocin binds its receptor in myoepithelial cells of the mammary gland, activating a G_q protein which in turn activates PLC-β. This causes the cleavage of PIP₂ into DAG and IP₃. DAG stimulates PKC and IP₃ stimulates a rise in intracellular calcium, which disinhibits the contractile reflex in myoepithelium.

REVIEW the role of prolactin in lactation.

Prolactin (and hPL) is involved in the first three of four stages in lactation: 1) milk synthesis, 2) lactogenesis, and 3) galactopoiesis. The fourth stage, milk ejection, is under the control of oxytocin.

DESCRIBE the actions of oxytocin on uterine smooth muscle.

In the myometrium, oxytocin binds its receptor and through G_q triggers the activation of PLC-β and PLA₂. PLC-β acts as described above, resulting in the rise in intracellular calcium, aiding the stimulus for uterine contraction. PLC₂ catalyzes the conversion of phospholipids (e.g. PIP₂) into arachidonic acid, a precursor for prostaglandins (principally PGE₂ and PGF_2α) that aid in uterine distension and promote uterine contractions.

DESCRIBE the contributing roles for oxytocin and the oxytocin receptor in the generation of uterine contractions at term.

Estradiol stimulates the insertion of oxytocin receptors into the myometrium, which increases uterine sensitivity to oxytocin. As a result, low levels of oxytocin will cause substantial uterine contractions.

DESCRIBE the secretory stimulus for oxytocin at parturition.

At parturition, the estradiol:progesterone ratio is high. The combination of high estradiol with low progesterone stimulates the release of oxytocin from the posterior pituitary.

DISCUSS the similarities and differences in the signal transduction schemes regulating actions of oxytocin in mammary myoepithelium and uterine myometrium.

Both mammary myoepithelium and uterine myometrium use G_q protein-coupled receptors to respond to oxytocin. Similarly, both use the PLC-β second messenger system to result in intracellular responses to oxytocin. However, because uterine contractions result from prostaglandins, the uterus needs a way to respond to oxytocin with prostaglandin synthesis. For this reason, the binding of oxytocin to its receptor in the uterine myometrium also results in activation of PLA₂, which converts PIP₂ to arachidonic acid, the chief prostaglandin precursor.