Membrane-permeable Signals Flashcards
The simplest way for information to cross the plasma membrane
Signalling molecules diffuse passively through
2 types of signalling molecules that diffuse across the membrane
Gases (nitric oxide, NO; oxygen, O2)
Hydrophobic small molecules (steroid hormones)
Nitric oxide (NO)
NO mediates short-range signalling in the vasculature
Simple diatomic gas
High reactivity with heme or oxygen so short range of action
Where is NO made?
In endothelial cells by nitric oxide synthase
How does NO impact vascular smooth muscle?
Diffuses to smooth muscle (adjacent to endothelial cells and induces relaxation
Target of NO
Soluble guanylyl cyclase, which generates cGMP
Soluble guanylyl cyclase
Dimer containing a regulatory domain with a heme group
Soluble guanylyl cyclase in the absence of NO
Regulatory domain represses activity of catalytic domain
Soluble guanylyl cyclase in low levels of NO
NO binds to heme group (high affinity) and induces conformational change that partially activates the catalytic domain
Soluble guanylyl cyclase in high levels of NO
NO binds to low affinity binding site, full activating enzyme
Oxygen (O2) as a signalling molecule
O2 binding regulates response to hypoxia
Short-term hypoxia
Forces a shutdown of inessential processes that consume ATP and an increased rate of anaerobic glycolysis
Longer-term hypoxia
Induces transcriptional changes leading to responses such as angiogenesis
How are transcriptional responses to hypoxia mediated?
HIF-alpha
HIF-alpha in normal O2 levels
HIF-alpha degraded -> binding of O2 to heme groups activates proline hydroxylase domain (PHD) proteins, which hydroxylate prolines on HIF-alpha. This allows binding of ubiquitin ligase, which adds long chains of ubiquitin to HIF-alpha, targeting it for degradation
HIF-alpha in low levels of O2
PHD proteins inactive so no degradation of HIF-alpha
HIF-alpha accumulates in the nucleus and promotes the transcription of hypoxia-dependent genes
HIF-alpha and cancer
HIF-alpha is overexpressed in many human cancers. particularly solid tumours.
Implicated in promoting tumour growth by initiating the growth of new blood vessels (angiogenesis) that deliver O2 and nutrients to tumours
Clinically, elevated levels of HIF-alpha have been associated with aggressive tumour progression and increased mortality
Hydrophobic small molecules - examples
Steroid hormones
Vitamin D
Thyroid hormone
Retinoic acid
What types of receptors work for hydrophobic small molecules?
Transcription factors of the nuclear receptor subfamily
Nuclear receptors structure
N-terminal DNA binding region and C-terminal ligand-binding region
Class I nuclear receptors - examples
Oestrogen
Progesterone
Testosterone
Glucocorticoid receptors
Class I nuclear receptors when ligands aren’t presents
Nuclear receptors are in cytosol in complex with other proteins (some of them heat shock proteins)
Associated proteins prevent receptor being degraded and keep it in an inactive conformation
Class I nuclear receptors - ligand binding
Ligand binding causes conformational change – dissociation of repressor proteins, and dimerization with another receptor
Receptor dimer is imported into the nucleus – DNA-binding domain binds DNA, binds coactivator proteins (such as chromatin remodelling complexes including histone acetyl transferase, HAT)
Transcription of hormone-responsive genes
Class II nuclear receptors - examples
Retinoic acid
Thyroid hormone
Vitamin D receptor
