Week 2 Flashcards
Hormonal control
- Essential characteristic of multicellular organisms is cell differentiation & division of labour
- Specialised functions of the tissues and organs in complex organisms
- Hormonal and neuronal signals integrate and coordinate many many activities within the organism
Neural Communication
- can travel long distance
- really, really fast
- target cells = very specific (synapse), nerve, muscle & gland
Hormones
A chemical substance produced in the body that controls and regulates the activity of certain cells or organs
- Many hormones are secreted by special glands, eg thyroid hormone - thyroid gland = endocrine hormones
- Hormones are essential for every activity of life - development, metabolism, growth, reproduction, behaviour etc
Endocrine Communication
- long distances - transport via bloodstream
- Hormones secreted by glands
- Target organs or cells— cells that have receptors for a hormone and can respond to it
Neuroendocrine Communication
- Combined neural & endocrine signalling
- Neuron secretes hormones into blood
- Adrenal medulla - modified postganglionic neurons (adrenaline)
- Posterior pituitary - axonal projections from hypothalamus (oxytocin)
How does studying hormones present challenges?
-
Produced in small amounts, so difficult to purify in appreciable quantity
• Chemical analysis of thyrotropin-releasing hormone (TRH) required extraction of the hypothalamus from one million pigs - ELISA was developed to be a more sensitive way to measure hormones
The ELISA (Enzyme-Linked immunosorbent Assay)
Can detect and/or quantify hormones
- Coat well with sample (antigen is hormone)
- Incubate with primary antibody against specific antigen
(hormone) - Incubate with secondary antibody-enzyme complex (if required)
- Substrate converts to detectable product (colour)
- Quantify hormone
Protein/peptide Hormones
- Large group
- Stored in secretory granules or vesicles = exocytosis release
- Hydrophilic –bind cell surface receptors
Rapid acting, short lived
Steroid Hormones
- Derived from cholesterol. Include: cortisol, aldosterone, testosterone and progesterone.
- Lipophilic: require transport proteins & bind intracellular receptors
- Stored in granules & present in free form in cytoplasm
Tyrosine-derived Hormones
Catecholamines: Adrenaline and NA - secreted by the adrenal medulla
Thyroid hormones – Thyroxine
Dopamine
- Catecholamines + DA – water soluble (extracellular Rs, ~50% of CAs use transport protein)
- TH - lipid soluble (>99% use transport proteins, intracellular Rs)
- TH stored in granules & present in free form in cytoplasm. CA stored in secretory granules
Hormone Transport
- The released endocrine hormones enter the blood - circulate in two forms:
• Free (unbound)
• Bound: carried by specific albumins and globulins which are synthesised in the liver. - In general, steroid and thyroid hormones are bound to transport proteins
- Polypeptide hormones circulate in a free form.
The Major Endocrine Glands
• Brain: hypothalamus, pituitary
• Thyroid, parathyroid
• Adipose (fat) tissue
• Adrenals (on top of the kidneys)
• Pancreas
• Ovaries/Testes
Cells in isolation
• survival depends on an elaborate communication network
• cells adjacent to one another frequently communicate through cell-cell contact
• other forms of communication cover larger distances = extracellular signaling molecules
Receptor
A membrane-bound or soluble protein. Or protein complex, which exerts a physiological effect (intrinsic effect) after binding its natural ligand
A multi domain protein consisting of:
- a hormone binding domain (specifies which hormone bonds)
- signal-transduction domain (varies between which receptor type but essential)
- transmembrane domain (in most but not all)
Typical ligands
- Small ions (ferric ion; bacterial ferric receptor)
- Organic molecules (adrenaline; epinephrine receptor)
- Polysaccharides (heparin: fibroblast growth factor)
- Peptides (Insulin: insulin receptor)
- Proteins (Vascular endothelial growth factor: VEGF receptor)
Contact-dependent
Contact dependent signalling requires cells to be in direct membrane- membrane contact
Juxtacrine
Cells respond to signal present on the surface of another cell. Requires physical contact between the two cells.
This type of signalling is seen in apoptosis or cell death where immune cells kill infected (e.g. virus) or ‘tumour’ cells or during the phagocytosis of dead cells e.g. removal of dead cells by macrophages
Paracrine
Paracrine signalling depends on local mediators that are released into the extracellular space & act on neighbouring cells.
Signalling cell synthesises and releases hormone to receptor of target cell which is in close proximity (or even adjacent)
Synaptic
Synaptic signalling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses
Endocrine
Distant Target cells have specific RECEPTORS that bind the hormone.
Major endocrine glands include, hypothalamus, adrenal, thyroid, pancreas, ovaries/testes
Hormone synthesised and released into blood by the cells of the endocrine gland
The target cell is situated a long distance from the source of the hormone
Classification of Hormones (by chemical properties)
- Small lipophilic (not water soluble but lipid soluble)
- Hydrophilic (water soluble)
- Large lipophilic (too large to diffuse across membranes)
Small Lipophilic
- transported in blood bound to carrier proteins
- can diffuse through membranes
- can have both nuclear and cytosolic receptors
e.g. steroid hormones (corticoids, oestrogen)
Hydrophilic
- not able to diffuse through membranes
- have receptors ON the membrane
- a diverse group
e.g. polypeptides (insulin), small charged molecules (adrenaline)
Large Lipophilic
- have receptor ON the membrane
E.g. prostaglandins
7 steps for specific and efficient info transfer
- Synthesis
- Release
- Transport
- Detection
- Transduction
- Target cell response
- Termination
- Synthesis
Synthesis of the hormone
- a hormone must be produced by a cell
(this synthesis may be a regulated process i.e. only made when needed)
- Release
Release of the hormone
- after synthesis the hormone must leave the cell that made it
(this release may be regulated)
- Transport
Transport to the target cell
(a target cell is able to respond to the hormone) after release the hormone must get to where it is supposed to be acting
- Detection
Detection of hormone by the target cell
- this requires SPECIFIC binding of the hormone by the
cell-receptors of the target cells
- Transduction
Transduction of the signal from the receptor this MOVES the signal from OUTSIDE -> INSIDE
(therefore from extracellular to intracellular - possibly even to the nucleus of the target cell)
- Target cell response
Target cell response
- METABOLISM
- GROWTH
- DIFFERENTIATION
- Termination
Termination of the signal if the signal is not stopped then the response does not stop
Define Binding Specificity
Measure of the ability of the receptor to distinguish between closely related substances
- binding specifically is crucial for good health, hence receptors bind very specifically to the hormone
Functions of receptors
- Binding a hormone with high affinity
- Invoking a signal inside the cell to initiate a biological response
- in the absence of the hormone the receptor does not convey and information = INACTIVE
- changes in receptor conformation allow changes in interaction with other molecules inside cell = ACTIVE
Receptor Binding Studies
- receptor binding of a hormone is specific, thus the receptor is a HIGH-AFFINITY binding protein
(Similarities can be drawn with enzymes and how they can bind their substrates through specific interactions) - the interactions of a Hormone (H) and Receptor (R) are HIGHLY-specific (involves non-covalent interaction - ionic and van der Waals)
- Binding induces CONFORMATIONAL CHANGES in the receptor which is DETECTED by INTRACELLULAR MOLECULES
Nuclear receptor
Hormone binding allows the receptor to regulate the expression of specific genes
Signalling of Nuclear Receptors
• Steroid Hormones are derived from cholesterol by the stepwise removal of carbon atoms and hydroxylation
• Steroid hormones are synthesised in the adrenal cortex (the glucocorticoids and mineralocorticoids) and also the gonads (for oestrogens, progesterone, androgens)
NR signalling molecules
- are small hydrophobic, lipid soluble
- can diffuse through the membrane of target cells
- bind to intracellular receptors
- all function in the same basic manner
- binding to the intracellular receptor affects the cells ability to transcribe specific genes
- interact DIRECTLY with the transcription factors they control
NR domain structure
• Central DNA-binding domain - the part which binds DNA
• Ligand binding domain (SPECIFICITY) - hormone dependent activation (or repression)
• Variable N terminal domains which may contain one or more activation domains - to alter gene transcription
Receptor Activation
• Receptors, in their inactive states, are bound to inhibitory proteins e.g. ER is bound to heat shock proteins (hsp90)
• Binding of ligand induces a conformational change releasing the inhibitory protein and binding a co-activator protein to induce gene transcription (co-repressors e.g. tamoxifen)
• Receptors can be located:
1) in the cytosol (e.g. estrogen receptor) and are transported to the nucleus after the ligand is bound
2) in the nucleus (thyroid and retinoid receptors)
Nuclear Receptor Response Elements
The nucleotide binding sequence that interact with nuclear receptors are called response elements
- the response elements lie adjacent to the genes that the hormone (ligand) regulates
- they consist of 6 base pair (sometimes inverted) repeat sequences separated by 3-5 base pairs
