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• Five secretory cells producing 6 different hormones– Cortocotroph
• ACTH– Gonadotroph
• LH and FSH– Somatotroph
• GH– Lactotroph
• Prolactin– Thyrotroph
• TSH
ACTH
• Part of larger protein– Pro-opiomelanocortin
• One gene (8kb, three exons and two introns)
– Codes for one large protein
• Transcription of gene– Activated by CRH,
arginine vasopressin, cytokines
– Inhibted by glucocorticoids
• Transcription of POMC gene– CRH type 1 receptor
• Production of cAMP and activation of protein kinase A pathway
– Activation of CREB transcription factor
• Activation of MAP-Kinase pathway
– Cytokine receptor (LIF)• Activation of JAK/Stat pathway
– Interaction with CRH signaling pathway
• Pro-opiomelanocortin– 266 amino acids– Proteolytically cleaved
to produce corticotrophic, opioid, and melanotrophic peptides
• Secretion of ACTH– Complex regulation
through HPA (hypothalamus-pituitary-adrenal) axis
– Circadian and ultradian rhythm
• Hypothalamic control (CRH)
– Activity of nuclei regulated by glucocorticoids
• Pulse amplitude rather than frequency determines circadian rhythm
Regulation of ACTH secretion
• Exercise (short and exhausting)– Increased secretion of ACTH
• Hypercortisolism in athletes
• Stress– Increased production of cortisol
• Integration of information received by the CNS• Constrain the inflammation
Action of ACTH
• Primary function– Proper maintenance of adrenal gland– Adrenal steroidogenesis
• Cholesterol transport• Conversion to pregnenolone• Inhibited by glucocorticoids
Gonadotropins
• Two hormones from one type of cells– LH and FSH
• Glycoprotein hormones– Two subunits
• Alpha– Universal among all glycoprotein hormones
• Beta– Hormone specific
• Combination of alpha and beta subunits– Essential for biological activity
Synthesis of gonadotropins
• Alpha subunit– Generated from different gene
• Chromosome 6
– Increased synthesis by GnRH and TRH
• Beta subunits– Determinant of biological activity
• LH beta on chromosome 19• FSH beta on chromosome 11
• Transcription of LH beta subunit mRNA– GnRH– SF-1– Estrogen
• Transcription of FSH beta– Role of GnRH and steroids
• Unclear• Different promoter structure from LH
Regulation of gonadotropin secretion
• Pulsatile secretion– Mirror image of GnRH pulses
• Frequency and amplitude• LH more sensitive to changes in GnRH
• Gonadal steroid hormones– Testosterone
• Inhibits secretion• Enhances FSH beta subunit mRNA transcription
– Estrogens• Dual function (stimulatory/inhibitory)• Cyclic changes in female during reproductive cycle
• Gonadal peptides– Inhibins
• Inhibits secretion of FSH
– Activins• Stimulates FSH secretion and action
– Follistatin• Inhibits FSH secretion and action
Function of gonadotropins
• Receptors for LH and FSH– Highly homologous
• 50 % of extracellular domain• 80 % of transmembrane domain
• Steroidogenesis in male and female– cAMP production
• Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR)
• Increased enzyme activity
Function of gonadotropins
• Receptors for LH and FSH
• Steroidogenesis in male and female– cAMP production
• Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR)
• Increased enzyme activity• Development and function of gonadal cells and
gametes– FSH
Growth hormone
• Human GH gene– Located in chromosome 17
• 66 kb in length• Cluster of genes that encode closely related genes
– GH-V– Placental lactogen/chorionic somatotropins
– Transcription of GH mRNA• POUF1 transcription factor
– Pituitary specificity– Interacts with protein kinase A pathway
• Large polypeptide hormone– 191 amino acids
• Four alpha helices looped together
• Interacts with binding protein (GHBP)– Extends half-life of GH– Found in rodents, rabbits,
and humans• Extracellular domain of
GH receptor in human and rabbit
• Product of alternative transcription in rodents
Regulation of GH secretion
• Major GH pulses (70 % of total daily output)– Slow sleep (deep sleep)– Age-related loss of GH
• Decrease quality of sleep
• Obesity and diabetes– Decreased GH release– Nutritional status
• One of the major regulatory factor of GH secretion
• Hormones– Steroids
• Acute elevation in glucocorticoids (+)• Chronic elevation in glucocorticoids (-)• Gonadal steroids (+)
– Thyroid hormones• Inhibitory
Action of GH
• Growth and metabolism– Action mediated by IGF-I
• Mediation of growth• Endocrine IGF-I
– Liver
• Local (autocrine/paracrine) IGF-I
• Gender-specific pattern of GH secretion– Affects amount of steroidogenic enzymes
• Gender-specific pattern of steroidogenesis
– Gender-specific pattern of liver enzyme expression
– Gender-specific action of GH• Mediated by STAT 5b activity
TSH
• Glycoprotein hormone– Alpha and beta subunits
• Alpha is identical to that of gonadotropins• Thyrotroph-specific expression
– Different region of gene promoter
– Gene for TSH beta subunit• Located on chromosome 1• Transcription regulated by Pit-1
• Post-translational modification– Glycosylation
• Affects proper molecular folding • Combination of alpha and beta subunits• Regulated by TRH (+) and T3 (-)
Secretion of TSH
• Bioactivity of TSH– Glycosylation
• Clearance rate
• Pulsatile secretion– Not as pronoused as gonadotropins or GH
• Low variation in concentrations
– Circadian pattern• Increased secretion during night
– Independent of sleep
• Hormonal regulation– Major factor of TSH secretion
• Thyroid hormone concentrations– Extremely important
• TRH• Dopamine (-)• Glucocorticoids (-)• SS (-)
Action of TSH
• Thyroid hormone production– G-protein coupled receptor
• Thyroid cell integrity maintenance
Prolactin
• Structurally similar to GH– Common ancestry
• Chromosome 6
• Prolactin gene expression– Estrogen– Dopamine– TRH– Thyroid hormones
• Exits as monomer or polymer in circulation– 23 kDa (monomer)
• Most bioactive
– 48-56 kDa (dimer)– > 100 kDa (polymer)– Glycosylated
• Less active
• Binds to prolactin binding protein
Regulation of prolactin secretion
• Inhibitory– Hypothalamic
• Dopamine• Calcitonin
– Paracrine factors• Endothelin-1• TGF-beta 1