Neurohypophysial Hormones Chapter 7 Neurohypophysis Magnocellular neurons Pars

Neurohypophysial Hormones Chapter 7

Neurohypophysis • Magnocellular neurons – Pars nervosa – 2 pr hypothal nuclei (fig 7. 1) – Hold secretory granules • Neurohemal • Traverse down infundibular stalk • Post pit from neural ectoderm – Pituicytes; mostly glial

Neurohypophyseal Hormones • Oxytocin (OT), Arg Vasopressin (AVP; ADH) – Structurally related – 9 aa’s; disulfide bridge; 3 aa tail (carboxy term) • Genes for precursor prot’s – Chromosome 20 – Gene duplication (? ) – Opp DNA strands

• Close assoc’n w/ neurohypophysin – Posttransl’n cleavage prod of proprot • Cleavage w/in sec granule – One for each hormone – Complex before excr’n – No physio action – May be transporters • PVN cell bodies mostly prod OT; SON cells bodies mostly prod AVP – Both types found in each region – Species differ

Hormone Release • Stim signals – Body sensory receptors • OT: breast; AVP: blood vessels • Afferent neurons spinal cord, other pathways SON, PVN cell bodies – Rostral midbrain connections SON, PVN • Exc – cholinergic; Inh – noradrenergic – Interneurons near secretory neurons may modulate

• Release w/ depol’n axons – Neurosec granules fuse w/ cell membr – Ca impt – Hormones vessels • OT may encourage own release – OT in SON, PVN incr’d OT release – PRL impt

Vasopressin Regulates Body Fluids • ECF/ICF – Homeostasis protection ICF, cell components – IVF easiest to control • Why blood? • Why maintain blood pressure?

• BP can be maintained through IVF vol – Or through art smooth muscle contraction • Fluid vol control through kidney – Prox tubule: most reabs’n most water, electrolytes • Luminal membr renal endothelium has water channels (aquaporins) – Distal tubule, collecting duct can become permeable to water w/ hormonal signal • Vasopressin

Vasopressin • Human arg in position 8 • Coexpressed w/ CRH in parvocell paraventric neurons – Potentiates CRH response @ corticotrophs • Can function as neurotransmitter – Antipyretic (lowers body temp) • Receptors heptahelical, G-prot coupled

Osmoregulation • If incr’d body fluid osmolality (mostly Na) – stim’n hypothal osmoreceptors • Not related to SON, PVN prod’ng cell bodies • Sensitive to blood [electrolyte] changes – Stim’d @ plasma osmolality >280 m. Osm/kg • Specific – Na. Cl, sucrose – Not glucose, urea – AVP rel’d

• If decr’d blood vol, pressure – stim’n baroreceptors • Heart LA, aortic arch, carotid sinus • Afferent signal vagal, glossopharyngeal nerves • Stim’n when bp decr’d >8% – AVP released

• Other AVP regulators – Renin-angiotensin system • Na, so fluid osmolarity – CNS symp input • Book: both receptor signals impinge on AVP-producing cell bodies • Overall: AVP incr’d bp by – Retention of water – Incr’d contraction vasc smooth muscle

Mechanism of Vasopressin Action • In kidney collecting duct epithelium • V 2 renal receptor; ad cyclase coupled – Four subtypes – Others through inositol/Ca • Book: toad bladder model – Epith sheet – Basal water barrier @ mucosal side • Analogous to renal tubule lumen • Other: serosal

• AVP @ serosal side – change in water permeability – barrier decr’d – water transport mucosal to serosal • Withdrawal AVP reversal

• In nephron collecting duct – Basal level water barrier @ luminal (apical) side – Endothelial cell vesicles in subapical area • Contain prot’s that can form water channels (aquaporins) – Membr-integral prot’s – 9 identified – Type 1 (AQ 1) in prox tubule • Type 2 aquaporins – Exclusive to renal collecting duct endothelium – Biosynth • By AVP • Via CREB-mediated transcrn’l control

• AVP interaction w/ V 2 receptor (fig 7. 15) – ad cyclase activation – incr’d c. AMP – act’n PKA phosph’n AQP 2 mol’s – translocation vesicles • Actin filaments, dynein – fusion endosomal vesicles w/ apical membr – AQP 2 insertion into apical membr’s • PKA act’n also stim’s synth AQP 2 prot’s – Through c. AMP-linked Response Element

• Now water moves w/ concent gradient – Dilute urine collecting duct endothelial cells • Another AQP (type 3; also 4? ) found in basal (serosal) membr – Allow water ISF IVF – ISF here highly concentrated • Antiparallel to ascending limb of nephron loop • Impt to urine concent – AQP 3 induced w/ dehydr’n (not linked w/ AVP) • AVP also regulates urea concent in kidney medulla (impt to urine concent)

• AVP also – Stim’s release ACTH release cortisol • Synergistic w/ CRH – Stim’s release TSH; may regulate • Equipotent w/ TRH • AVP incr’s bp by regulating contraction vasc smooth muscle – Through tyr phosphorylation of enzyme-active receptor • V 1 vascular receptor

Oxytocin Activity Related to Reproduction • Several functions – Milk release – Uterine contraction at parturition – Vascular smooth muscle response – Maternal/mating behavior • Most specific to females • Transitory

Oxytocin Hormone • Nonapeptide • Secr’n stim’d by – Cervicovaginal stretch receptor act’n – Stim’n nipple, clitoris – Psychosensory input (lactating women) – Dehydration, stress (AVP) • Secr’n inhib’d by – Ethanol

• OT receptor – Encoded by chromosome 3 – Heptahelical – G-prot coupled (Gaq) – PLC signaling pathway incr’d Ca (from stores + extracell)

At Mammary Gland • Suckling – act’n sensory nerve endings – afferent signals through spinal cord hypothal – OT release • OT mammary gland myoepithelial cells (fig 7. 4, 7. 5) – Binding OT receptors incr’d intramammary pressure – milk expresion to ducts, alveoli, nipples

At Uterus • Descent fetus – cervical/vaginal stretch receptor act’n – OT release from post pit • Positive feedback mech til birth • Get incr in both freq, amplitude of contractions

• Near parturition (20 -39 wks), uterine myometrium more sensitive to OT – E 2 incr’d OT uterine receptors incr’d OT sensitivity – Progesterone low; can suppress OT receptor synth – BUT circ’ng OT not nec for labor initiation, maintenance • Uterine OT m. RNA incr’d more in pregnancy than hypothal (rat) • Uterus may be autocrine

• OT binding myometrium receptors – inhib’n Ca ATPase Ca out of intracell stores – IP 3 involvement Ca out of intracell stores – (with incr’d intracell Ca) act’n Ca membr channels • depol’n myometrial cells open voltage-gated channels • influx extracell Ca

• Prolonged elevation intracell Ca – calmodulin act’n – kinase act’n – phosph’n myosin – contraction

• Also OT interacts w/ receptors in both myometrium + endometrium – synth PGF 2 a (ovine endometrium) • Incr smooth muscle contraction – Estrogens incr’d activity PG synthetase, so enhance PGF 2 a • OT-induced myometrial contractions also endometrial PGF 2 a induction

• Progesterone involvement – Antagonizes estrogen effects – Maintains endometrium (pregnancy) – Is maintained by CL • OT uterus PG’s – CL luteal regression – decr’d progesterone – depress maintenance of pregnancy

• Also, now decr’d progesterone decr’d antagonism of estrogen effects – incr’d PGF 2 a in endometrium, – incr’d OT-induced PGF 2 a in myometrium • Overall, incr’d uterine contraction

Vascular Smooth Muscle • OT may constrict or relax – Depends on site – May be distinct receptor types for 2 responses • Some cross-over w/ AVP – More OT receptors in umbilical vasc – More AVP receptors in aorta vasc

Maternal Behavior • OT incr’d maternal behavior in virgin females (rat) – May need E 2 – Ovariectomization negates effect • OT may be rel’d @ many brain sites at parturition – Acts as neurotransmitter – Inhibits memory/retrieval (? ) • Opp AVP • Block recall pain of labor

Mating Behavior/Sexual Response • Hypothal VMN controls some female mating behavior – E 2 induction OT receptors – Progesterone • incr’d OT receptor binding • expansion brain area covered by receptors • Plasma [OT] incr’d during sexual arousal (human) – Female – incr’d uterine, vaginal smooth muscle – Male – incr’d repro smooth muscle contraction

Other OT Activities • Inhib CRH-mediated ACTH secr’n (human male) – Stress response? • Stim release PRL – PRL needed to produce milk • Book: control feeding behavior