REGUB2: Cellular Mechanisms of Hormone Action (i)

Intro

hormones = chemicals released by cells that impact on gene expression/protein state. They complement NTs (adjacent contact, broadcast message)

Hormonal signalling can be...

autocrine (act on same cell)

paracrine (act on adjacent cells)

endocrine (act on distant cells)

Hormones are specific + potent through Rs

Factors influencing degree of response

1) delivery of hormone

synthesis/secretion rate

target proximity

dissociation constants with transport proteins

rate of conversion to active

clearance rate by liver/kidney

2) R/Tissue Status

density/ state of occupancy

Hormone Classification

1) by chemical nature

steroid hormones (eg cortisol)

protein/peptide hormones (eg PTH)

glycoprotein hormones (eg LH)

iodothyronine (eg T3+T4)

2) by R type

intracellular

cell surface

3) by secondary messengers

cAMP

cGMP

kinase

phosphatase

Signalling

4) by solubility

group 1 = hydrophobic

group 2 = hydrophilic

steroids, iodothyronines, calcitriol

protein carrier bound in plasma

long T1/2

intracellular R

slow development effects

mediator = Hormone-R complex

peptides/proteins, catechols

free in plasma

short T1/2

cell surface R

rapid metabolic effects

mediator = second messenger

Group 1

1) diffusion

2) bind to R

3) translocation

4) bind to hormone response element

5) mRNA + protein expression

Group 2

1) bind via GPCRs on membrane

2) intracellular secondary cascade (propagates + amplifies signal)

3) cAMP activates PKA

4) selective protein phosphorylation by phosphodiesterase enzymes

ensure rapid cAMP turnover

ensure rapid termination once hormone is removed

regulated by cAMP,cGMP,hormones,Ca2+

Hormone response elements

regions of DNA close to transcription start site (upstream/5')

associate with nuclear Rs as well as activated Rs

adds further complexity/control

Other secondary Rs

Ca2+

activates phospholipase C

produces IP3

Ca2+ channels open

intracellular conc decreases

cGMP

GPCR independent

driven by granulate cyclase (membrane bound R)

produces ANF

causes smooth muscle relaxation + decreases BP