WEEK 5 (Paracrine and hormonal communication) Flashcards
Define Cytokines
A collection of protein signal molecules secreted by cells of the immune system and other cell types that largely act locally to regulate immune responses
Define Eicosanoids
A group of lipid signal molecules derived from a fatty acid in the plasma membrane of most cell types that act locally to regulate diverse cellular processes throughout the body
What are Cytokines?
Intercellular regulatory proteins secreted primarily by white blood cells and other cells of the immune system but also by some non-immune cells
What non-immune cells are prolific producers of cytokines?
- endothelial cells (line blood vessels)
- fibroblasts (form the extracellular matrix in connective tissue)
- adipose tissue cells (store excess fat)
What are the functions of cytokines?
- regulate numerous activities of the immune system (e.g mediating inflammation, enhancing the activity of antibody-producing cells and virus-fighting cells)
- influence cell growth and cell differentiation during embryonic development
- regulate wound healing
What are growth factors?
Cytokines important in development
Describe how cytokines function
- typically act locally as paracrines but some travel in the blood, similar to hormones, to distant target cells to produce systemic (bodywide) responses
- function primarily by binding to receptor-enzyme complexes
Which pathways do immune cytokines and growth factors usually use?
Immune cytokines largely employ the JAK/STAT pathway
Growth factors mainly use the tyrosine kinase pathway
Describe how Eicosanoids can be derived from the plasma membrane
Membrane-bound enzyme Phospholipase A2 splits Arachidonic acid from the plasma membrane and converts it into either Prostaglandins, Thromboxanes and Leukotrienes. The enzyme CYCLOOXYGENASE (COX) initiates the pathway leading to the formation of PROSTAGLANDINS and THROMBOXANES, whereas LIPOOXYGENASE (LOX) results in the generation of LEUKOTRIENES.
What is Arachidonic Acid?
a 20-carbon polyunsaturated fatty acid that is a precursor for Eicosanoids
Describe what happens once Eicosanoids are synthesised
- Eicosanoids diffuse out of the cell to serve as local extracellular messengers
- They bind with surface membrane receptors of their neighbouring target cells and initiate second messenger pathways
- After action, rapidly inactivated by local enzymes before they gain access to the blood; if they do reach the circulatory system, they are swiftly degraded on their first pass through the lungs so that they aren’t dispersed through the systemic arterial system
What are the roles of Prostaglandins in the Reproductive system?
- promote sperm transport by action in smooth muscle in the male and female reproductive tracts
- ovulation
- menstruation
- preparation of the maternal portion of the placenta
- promote contractions of the uterus
What are the roles of prostaglandins in the Respiratory, Urinary, Digestive and Nervous systems?
- Respiratory - promote dilation & constriction of respiratory pathways
- Urinary system - increase renal blood flow & increase excretion of water and salt
- Digestive system - Inhibit hcl secretion by stomach & stimulate intestinal motility
- Nervous system - influence neurotransmitter release and action, increase body temperature, intensify the sensation of pain
What are the roles of prostaglandins in the Endocrine, Circulatory, Immune system and Fat metabolism?
- Endocrine system - enhance cortisol secretion & influence tissue responsiveness to hormones
- Circulatory system - influence platelet aggregation & increase and decrease blood pressure
- Immune system - promote inflammation & development of fever
- Fat metabolism - Inhibit fat breakdown
What is the function behind Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen?
Inhibit Cyclooxygenase (COX) thus blocking the conversion of Arachidonic acid into prostaglandins for pain relief and fever reduction
What is the function of Thromboxanes?
Promote platelet aggregation and constrict blood vessels
What are the functions of Leukotrienes?
Involved in inflammatory responses and cause the airway constriction characteristic of asthma
Define Endocrinology
Endocrinology is the study of homeostatic chemical adjustments and other activities accomplished by hormones which are secreted into the blood by endocrine glands
How can hormones be classified?
- into chemical groups based on their solubility (hydrophilic or lipophilic)
- according to their chemical structure (peptides, amides and steroids)
What are the key characteristics of Hydrophilic hormones?
- highly water soluble and have low lipid solubility
- peptide/protein hormones consisting of specific amino acids arranged in a chain of varying length
- amines are amino acid derivatives which include two types of hydrophilic hormones (catecholamine & indoleamines) and one type of lipophilic hormone (thyroid hormone)
What is the difference between Catecholamines and Indoleamines?
Catecholamines are derived from the amino acid tyrosine and are largely secreted by the adrenal medulla
Indoleamines are derived from the amino acid tryptophan and are secreted by the pineal gland
________ is the only indoleamine hormone
Melatonin
What are the key characteristic of Lipophilic hormones?
- have high lipid solubility and poor water solubility
- include thyroid hormone and steroid hormones
- thyroid hormone is secreted by the thyroid gland and is an iodinated tyrosine derivative
What do the solubility properties of a hormone determine?
- how the hormone is synthesised, stored and secreted by the endocrine cell
- how the hormone is transported in the blood
- how the hormone exerts it’s effects at the target cell
Describe the processing of hydrophilic peptide hormones
1) Large precursor proteins (PREPROHORMONES) are synthesised by ribosomes on the RER and then migrate to the Golgi complex in membrane-enclosed transport vesicles that pinch off from the smooth ER
2) During their journey through the ER and Golgi complex, the preprohormones are pruned to active hormones
3) The Golgi complex packages the finished hormones into secretory vesicles that are pinched off and stored in the cytoplasm until an appropriate signal triggers their secretion
4) On appropriate stimulation triggered by specific stimuli, secretory vesicles fuse with the plasma membrane and release their contents to the outside by exocytosis. The blood picks up the secreted hormones for distribution.
Describe the processing of Lipophilic steroid hormones
1) Cholesterol is the precursor for all steroid hormones
2) Specific enzymes are required for a series of specific enzyme reaction that modify the basic cholesterol molecule for the synthesis of various steroid hormones
3) Once formed, the lipid-soluble steroid hormones immediately diffuse through the steroidegenic cell’s lipid plasma membrane to enter the blood
4) Some steroid hormones undergo further inter conversions within the blood or other organs where they are changed into more potent or different hormones
What are some differences between hydrophilic peptide hormones and lipophilic steroid hormones?
- Peptide hormones are stored, steroid hormones are not stored (only the hormone precursor cholesterol is stored within STEROIDOGENIC cells)
- The rate of steroid hormone secretion is controlled entirely by the rathe of HORMONE SYNTHESIS
- Peptide hormone secretion is controlled primarily by regulating the release of presynthesised stored hormone
What is the difference between the transportation of hydrophilic and lipophilic hormones?
Hydrophilic peptide hormones are secreted by exocytosis and dissolve in the blood plasma
Lipophilic steroids and thyroid hormones are secreted by simple diffusion and circulate to their target cells reversibly bound to plasma proteins in the blood (only the small, unbound, freely dissolved fraction of a lipophilic molecule can cross the capillary walls and bind with target cells receptors to exert and effect; the bound hormones provides a large reserve that replenishes the active free pool)
Catecholamines circulate 50% as a free hormone and 50% loosely bound to albumin (plasma protein that picks up any hormone)
Why can’t any other type of hormone apart from steroid and thyroid hormones be taken orally?
The digestive system does not secrete enzymes that can digest steroid and thyroid hormones therefore any other types of hormones would be hydrolysed by protein-digesting enzymes and convert them into inactive fragments
What is the difference between the location of receptors for hydrophilic and lipophilic hormones?
Hydrophilic peptides and Catecholamines bind with specific receptors on the outer plasma membrane surface of the target cell since they cannot pass through the lipid membrane
Lipophilic steroids and thyroid hormone bind with receptors inside the target cell since they can pass through the lipid membrane
What is the difference between the general means of hydrophilic and lipophilic hormone action?
Surface-binding hydrophilic hormones function largely by activating second-messenger pathways within the target cell which alters the activity of pre-existing intracellular proteins to produce the desired effect
Lipophilic hormones function mainly by activating specific genes in the target cell to cause formation of new intracellular proteins to produce the desired effect. Proteins may be enzymatic or structural.
Describe what an inactive G-protein consists of
A complex of alpha, beta and gamma subunits with a GDP molecule bound to the alpha subunit
Describe how G-protein receptors work
1) extracellular messenger (first messenger) binds with its receptor which attaches to the associated G-protein coupled receptor, resulting in the release of GDP from the G-protein complex
2) GTP attaches to the alpha subunit which activates the G protein
3) Once activated, the alpha subunit breaks away from the G-protein complex and moves along the inner surface of the plasma membrane until it reaches an effector protein
4) The alpha subunit links up with the effector protein and alters its activity
Describe the Cyclic AMP second-messenger pathway
1) Binding of extracellular messenger to receptor activates a G protein, the alpha subunit shuttles to and activates adenylyl cyclase
2) Effector protein is ADENYLYL CYCLASE which is located on the cytoplasmic side of the plasma membrane. ADENYLYL CYCLASE converts intracellular ATP to cAMP by cleaving off two of the phosphates
3) cAMP activates protein kinase A (PKA)
4) Protein Kinase A phosphorylates an inactive designated protein, activating it
5) Activated protein brings about the target cell’s ultimate response to the first messenger
What happens once the response is completed in the cAMP second-messenger pathway?
- alpha subunit cleaves off a phosphate, converting GTP to GDP, and rejoins the alpha and gamma subunit to restore the inactive G-protein-complex
- cAMP and other chemicals are inactivated
- cAMP is degraded by PHOSPHODIESTERERASE
Describe the Ca2+ second-messenger pathway
1) Binding of extracellular messenger to receptor activates a G protein, the alpha subunit of which shuttles to and activates PHOSPHOLIPASE C bound to the inner side of the membrane
2) Phospholipase C hydrolyses PHOSPHATIDYLINOSITOL BIPHOSPHATE (PIP2) into DIACYLGLYCEROL (DAG) and INOSITOL TRIPHOSPHATE
3) Lipid-soluble DAG remains in the lipid bilayer of the plasma membrane but water soluble IP3 diffuses into the cytosol
following IP3:
3a) IP3 mobilises intracellular Ca2+ stored in the endoplasmic reticulum to increase cytosolic Ca2+ by binding with IP3 gated receptor-channels in the ER membrane
4a) Ca2+ activates CALMODULIN
5a) Ca2+ calmodulin complex activates Ca2+ calmodulin dependent protein kinase (CaM kinase)
6a) Activated CaM kinase phosphorylates designated proteins which allows them to bring about the desired response
following DAG:
3b) DAG activates protein kinase C (PKC)
4b) Protein kinase C phosphorylates designated proteins
5b) The resultant change in shape and function of these proteins activates them which produces the desired response
Why do so many cell types use the same complex system to accomplish a wide range of functions?
The cascading (multiplying) effect greatly amplifies the initial signal
Define amplification
The output of the system is much greater than the input
Describe Laron Dwarfism
The person is abnormally short despite having normal levels of growth hormone because the tissues cannot respond normally to growth hormone
Describe the lipophilic hormone pathway
1) Free lipophilic hormones diffuse through the plasma membrane of the target cell
2) Hormone binds to the specific receptor inside the cell (either in cytoplasm or in the nucleus)
3) Each receptor has a specific region for binding with its hormone and another for binding with DNA (can only bind to DNA once bound to hormone). Once bound, the hormone receptor complex binds with DNA at the HORMONE RESPONSE ELEMENT (HRE).
4) Binding of hormone receptor complex with DNA activates a specific gene within the target cell
5) Code of activated gene is transcribed into a complementary mRNA
6) New mRNA leaves the nucleus and enters the cytoplasm where it binds to a ribosome that mediates the assembly of new proteins
7) The newly synthesised protein is released from the ribosome and processed into a final folded form and produces the target cell’s desired response
What are nongenomic steroid receptor actions and how are they caused?
Nongenomic steroid receptor actions are actions accomplished by something other than altering gene activity (e.g changes in ionic influx across membranes)
They are caused when steroid hormones bind with unique steroid receptors in the plasma membrane alongside steroid receptors in the nucleus
What is the difference between the endocrine system and the nervous system?
The endocrine system secretes hormones into the blood for delivery to distant sites of action via the bloodstream
The nervous system transmits electrical impulses to the skeletal muscles and the exocrine glands that it innervates
What do the endocrine system and the nervous system have in common?
They both alter their target cells by releasing chemical messengers that binds with specific receptors of the target cells (neurons release neurotransmitters and hormones bind to endocrine cells)
What are the properties of the nervous system?
ANATOMIC ARRANGEMENT: a “wired” system: a specific structural arrangement exists between neurons and their target cells, with structural continuity in the system
CHEMICAL MESSENGER: neurotransmitters released into the synaptic cleft
DISTANCE: short distance (diffusion across synaptic cleft)
SPEED: rapid
DURATION: Brief
MAJOR FUNCTIONS: coordinates rapid, precise responses
What are the properties of the endocrine system?
ANATOMIC ARRANGEMENT: a “wireless” system: endocrine glands are widely dispersed and not structurally related to one another or to their target cells
CHEMICAL MESSENGER: hormones released into the blood
DISTANCE: long distance
SPEED: slow
DURATION: long
MAJOR FUNCTIONS: controls activities that require long duration rather than speed
Describe the specificity of action on the target cell for the nervous system
Dependent on the close anatomic relationship between neurons and their target cells
explanation: Many different muscles use the same neurotransmitters therefore these need to be released only to specific adjacent target cells and then swiftly inactivated or removed otherwise it can cause unwanted movement
Describe the specificity of action on the target cell in the endocrine system
Dependent on the specificity of target cell binding and responsiveness to a particular hormone
What makes the endocrine system suitable for regulating metabolic activities that require long-term stability?
Hormonal action is slow and prolonged
