Lecture 4- peptide and steroid hormones synthesis and

hormone

substance released from endocrine gland into circulation and transported to distant organ where it exerts specific action

molecular varieties of hormone

• GPCR ligands e.g. vasopressin, growth hormone, parathyroid hormone

• receptor tyrosine kinase ligands e.g. insulin

• steroids e.g. cortisol, aldosterone, sex hormones

GPCR ligands

• respond to polypeptide or modified amino acids

• change structural amino acid into signal through slight change

• tyrosine is amino acid, othrs are modified amino acids

amino acid multitasking

• tryptophan is an essential amino acid

• tryptophan can’t be made by itself

• when some amino acids are modified, they can produce 2 hormones

efficiency

• cost to getting tryptophan into the body, need to eat, digest and absorb into the body

• need a few enzymes to turn amino acid into hormones

• use chemicals already there instead of having completely new ones

• being less efficient makes it more adaptable

• adaptability in stressful environment important to adapt and evolve

peptide hormone formation and secretion - peptide hormone synthesis

• synthesised on ribosomes as prehormone or preprohormone, initial signal sequence 15-25 amino acids

• signal sequence binds to signal recognition particle

• complex binds to receptor to rough endoplasmic reticulum membrane

• signal sequence cleaved off, inactive storage form, further processing

• leader sequence directs the protein, allows protein to form correctly, gets cut off before secreting as mature protein

peptide hormone formation and secretion- formation of transport vesicles to transfer peptide to Golgi

• post-translational modification

• sorting and packaging of proteins to different places, use chaperones

• filter incorrectly synthesised proteins

peptide hormone formation and secretion - secretion(exocytosis)

• secretory granules translocate to plasma membrane, involves cytoskeleton(microfilaments and microtubules)

• docking and fusion of secretory granules with plasma membrane, involves docking and fusion proteins (SNAPS,SNARES,VAMPS)

• secretion is regulated

• rate of hormone secretion> > rate of synthesis

• vesicles dock at cell membrane, wait for signal to dock and fuse with membrane, signal usually intracellular calcium

biphasic secretion of peptide hormones

• 2nd wave of secretion due to non docked granules

• adrenaline creates a short spike

• more extended period of secretion keeps vesicles docked longer

peptide hormone action

• transported via circulation

• bind with high affinity and specificity to cell surface receptors on target cell

• hormone binding, conformational change in receptor, relayed to effector, generation of intracellular signals, cellular response

• sequence can dissolve, aqueous can dissolve in blood

• some cells have extracellular space feeding into blood

receptor

plasma membrane protein with 3 functional domains- extracellular(hormone binding), 1-7 membrane spanning domains(hydrophobic amino acids), intracellular(effector function)

adenylate cyclase, cyclic AMP

• adenylyl cyclase converts ATP into cAMP

• GPCR has 3 different proteins, alpha, beta, gamma

• alpha binds to GDP when turned off, binds to GTP when on

• Gi inhibitory hormone, inhibits AC, lower cAMP

• need mechanisms that can modulate each other

• cAMP activates protein kinase A

• tyrosine, serine, threonine can be phosphorylated

• GPCR pathways involve serine and threonine more

• proteins phosphorylated on serin, threonine and tyrosine

calcium mobilising receptors

• cytosolic calcium maintained at low levels(10-7M)

• can pump big fluxes of Ca very quickly

• calcium floods in, contracts cell, pumps out, relaxes cell

• IP3 receptors on calcium store

• cells can be activated by rise in cytosolic calcium

Ca entry from extracellular fluid

• via membrane Ca channels

• receptor operated Ca channels e.g. H1 histamine receptor

• voltage sensitive Ca channels

• histamine directly couples to channel, opens pore, Ca can enter

• Ca channel kept shut at -70mV

Ca mobilisation from smooth endoplasmic reticulum

• phosphatidylinositol cleaved into inositol 1,4,5 triphosphate

• rise in cytosolic Ca detected by calcium binding protein

tyrosine kinase coupled receptor

• hormone binding, activation of tyrosine kinase, phosphorylation of target proteins on tyrosine residues, cascade of protein phosphorylation, cellular response

• span membrane once

• work as homodimers

• stimulate receptor, auto-phosphorylate each other

• small signal gets amplified, small amount of hormone to spark signal that turns into large response

• small amount of insulin affects the whole body

steroid hormones

• made from cholesterol

• cholesterol stabilises cell membrane

• insoluble in blood, need carrier proteins to transport them around the blood

• binding proteins specific to each steroid hormone

• enters the cell and has intracellular effects

steroid hormone synthesis

• made in adrenals

• hypothalamus secretes releasing hormone, signal for cholesterol esters

• all steroid hormones are very similar, can make one from another

• closely related and interchangeable

• don’t need vesicular fusion

• steroids not stored

• rate of synthesis=rate of release

• transported in protein bound form

mechanism of steroid hormone action

• expression of specific genes altered, increase or decrease specific cellular proteins, cellular response

• cellular response is slow and prolonged

• big burst of cortisol drives gene expression of a lot of cells

• adrenaline very rapid burst, no long term consequence