Neuroendocrine Receptors Flashcards
What are 2 types of neuroendocrine receptors
- Nuclear hormone receptors - steroid hormone receptors
- Somatostatin receptors
Nuclear receptor - Steroid hormones
- are small lipophilic molecules that can diffuse through cell membranes.
For example:
- testosterone
- estradiol
- progesterone
- glucocorticoids (“glucose + cortex + steroid) e.g. cortisol (human) or corticosterone (rodents)
- mineralocorticoids - e.g. aldosterone
- thyroid hormones
Steroid hormone receptor mechanism:
- hormone (H) circulates
- H released from binding globulin
- H freely diffuses across membrane
- Unoccupied steroid H receptors (SHR) are bound to HSP90
- H binding to receptor dissociates HSP90
- SHR complex dimerises
- SHR dimmer enters nucleus
- Regulates gene expression
These nuclear receptors and their hormones are not always about activation of gene expression - these can cause repression of a gene expression
- there are about 40 subtypes of steroid/ nuclear receptors and these have a diverse rename of functions, like body metabolism, energy homeostasis - glucose homeostasis.
Common structural elements of steroid receptors:
-
Genomic mechanisms of steroid signalling:
- regulate gene expression via the activation of nucleus
- each receptors have neuronal terminal domaine NTD which is crucial for the regulation of gene expression
- DNA- binding domain (DBD) binds to the hormone response element (HER) in gene- and this also regulates gene expression
- hinge domain (H) - together with the DBD are important for nuclear localisation
- hormone binding domain- are unique for each hormone and is next to the hinge domain
And the hinge domain together with the DBD (DNA- binding domain) are crucial for pulling the hormone receptor complex into the nucleus
** Receptors — NTD — DBD — H—Hormone binding domain (which is unique to each hormone).**
- Non-genomic mechanisms of steroid signalling:
- regulate other systems via G-proteins receptors (GPCR)
- which can regulate things like calcium entry which can results activation of multiple signalling pathways like protein kinase A or activation if PLC pathway leading to release of calcium from intracellular stores and activation of RAS, MEK and ERK pathways.
- some of these steroids hormones can also alter membrane flexibility which can have a knock- out effect altering the function of ATPease and some ATPease can be electrogenic and alter membrane excitability.
Genomic and non-genomic steroid signalling mechanisms can be tied together to later neurotransmission:
Tied together- it is possible that genomic activation by steroid hormone can alter neurotransmitter levels (for example) either altering the production or the storage of that neurotransmitter/ neurosteriod - so when the activation of receptors does occur the strength of the neurotransmitters can be altered
Non-genomic signalling actions/ molecules for example Estradiol:
- Estradiol has differing effect on the neurons within the pre-optic area of the hypothalamus
- it causes both excitation and inhibition:
When estradiol is introduced it can either:
rapidly reduce neural activity causing inhibition (reduced APs) or rapidly enhance neural activity causing excitation (increased APs) and neural activity (APs) returned to its normal rates as the estradiol is washed off.
This suggests that these non-genomic signalling actions/ molecules are:
- very rapid
- and mediated by some changes in the 2nd messenger system leading to the alteration of membrane ion channel activity.
Somatostatin receptors
Encoded by chromosomes 3q28
- produced as a larger peptide called preprosomatostatin then cleaved down to 15/20 amino acid peptide
Expressed within the:
brain
Somatostatin is expressed in somatostatin interneurons found in the hypothalamus - inhibits neuronal firing thereby modulating neural activity
pancreas
Somatostatin is made and released in pancreatic delta cells - inhibit insulin and glucagon secretion = glucose homeostasis
GI tract
Somatostatin is produced in the GI tract - inhibits the secretion of gastrin, secretin, cholecystokinin and vasoactive intestinal peptide (VIP) = involved in inhibition of acid secretion from the stomach
- these has half-life = 3 minutes
These somatostatin receptors are also know as the anti-hormone hormone
There are 5 types of somatostatin receptors (SSTR)
- SSTR1- 5
- SST2 is the only receptor that has 2 subtypes = SSTR2a/ 2b
- encoded by 5 different genes
- activation of these receptors overall has an anti-secretory function which usually mediated by 2nd messenger systems e.g. cAMP, activation of ion channels
Each SSTR has 7 transmembrane domains and an intracellular terminal which has multiple binding sites
These SSTR belong to G-protein coupled receptors family (GPCR)
These SSTR are expressed within the:
- CNS
- Gut
- Pancreas
- Pituitary
- Kidney
- Thyroid
- Lung
- Immune cells
SSRT are involved in complex level of regulation which is driven by homo and heterodimerisation of these SSTR for example:
Heterodimers with- dopamine receptors, opioid receptors and epidermal growth factors.
And activation of these complex receptors links to unique pharmacological properties - for example alteration to sensitivity of an agonist
Intracellular signalling of SSTRs (how is it mediated)
- these SSTR are GPCR and their activation leads to a downstream effect through 3 primary effector systems which are:
1. Inhibition of adenylate cyclase (AC)
- inhibition of AC —> reduces cAMP levels —> decreased PKA activity = inhibition of hormone secretion
- via Gi/o pathway
2. Modulation of ions channels
- SSRTs can affect ion channel activity via the Gi/o pathway
- this activates GIRK channels (inwardly rectifying potassium channels) and also inhibit voltage-gated calcium channels
- this regulates neuronal excitability and secretion by affecting potassium and calcium channels.
3. MAPK pathway
- SSTRs activate MAPK (mitogen-activated protein kinase) pathway - specifically ERK1/2 and/or PI3K/Akt signalling
- this influences gene expression, cell proliferation (cell growth and survival) and apoptosis
Application of Somatostatin leads to a rapid reduction/ inhibition in spiking frequency of a cell’s electrical activity and as the SSRT washes out the spiking frequency returns to normal.
Activation of SSRT causes:
- inhibition of hormone secretion - i.e. IGF1/ IGF2/ EGF/ insulin
- inhibition of cell growth
- enhanced apoptosis
Additionally activation of SSRTs are useful for the suppression of unwanted cell growth which helps counteract tumour growth and somatostatin analogs are often utilised as a therapeutic application for tumour growth.
Neuroendocrine tumors
Most commonly found in:
- GI tract
- Pancreas
- Lungs
- Adrenal gland
They can develop in the brain and the periphery.
- development of neuroendocrine tumors can result in hormonal hypersecretion
- around 80% of these neuroendocrine tumors express SSTRs- typically SSTR2
Clinically developed SST analogues
These are:
- Octreotide
- Lanreotide
- Vapreotide
- Seglitide
- Pasireotide
And these analogues has half-life of 0.5- 12 hours
Depending on drug preparation they can be administered:
- 2-3 x daily by sub-cutaneous injection
- intramuscular injection (every 10-28 days)
- slow release = slower absorption
- and these have continuous slow infusion that last over several hours
There is also a development of radiolabelled SST analogues which is utilised to detect primary tumors - but is still clinically debated
SST analogues mechanisms overview
SST analogues have a direct and indirect effect;
direct effect
- inhibition of cell progression
- induction of apoptosis
- inhibition of growth factors effects (links to inhibition of growth factor release and signalling)
indirect effect
- inhibition of angiogenesis —> reduced vascular endothelial growth factor release
- modulation of immune system —> inhibition monocyte activation
- reduction in metastatic potential —> reducing the fusion of carcinosarcoma cells through blood vessels.
