BMS2021 Cell-cell communication, hormones and signal transduction..docx

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Biomedical Sciences
Prof.Christina Mitchell

BMS2021 Cell-cell communication, hormones and signal transduction. Hormone action and cell signalling. Cell and tissues talk to each other via messengers or hormones. Cells and tissues communicate with each other by releasing or responding to secreted substances that aim in altering the specific function of a cell or tissue. These messengers are termed hormones. This communication is required for the development and organisation of tissues, the control of growth, division and death and coordinating the diverse cellular activities. This message system is termed the endocrine system. Hormones can be divided into 3 main classes; peptide/protein hormones, such as insulin, amine hormones, such as epinephrine and steroid hormones such as oestrogen or testosterone. The method in the way cells communicate occur in 3 ways, they can secrete chemicals that act on targets some distance away, the can display signalling molecules that are bound to the cell surface and influence other cells that make direct contact or they can form gap junctions that directly join the cytoplasm of interacting cells. In higher vertebrates, such as humans, evolution has developed a complicated set of hormonal controls that regulate cellular processes. Hormones can act to increase or decrease permeability of cell, thereby modulating the transport rate of molecules, they can influence the specific function of a cell by inducing/inhibiting synthesis of nucleic acids and proteins and they can modulate the metabolism of energy stores such as carbohydrates, fats and proteins. Hormones have a district set of properties that modulate their synthesis and action. They are produced in small amounts by the endocrine gland in question and that secretion rate is determined by the need for that hormone. They do not affect the organ that secretes the hormone itself. Depending on the hormone released, action may be general thought various cells in the organism or specific to target cells or tissues. The effect on tissues is dependent on the ability of the tissue to respond and the amount of hormone present. Steroid hormones are either adrenocortical steroids such as glucocorticoids and mineralocorticoids, or gonadal sterodisa such as androgens or oestrogens. These are all derivatives of sterane which had a completely hydrogenated phenanthere structure attached to a cyclopentane. Peptide/protein hormones, such as insuil, can be stored in secretory vesicles for up to one day. Many are stored as prohormones. They are released via exocytosis of secretory granules. This method of release is modulated by other hormones, metabolites and the CNS. They can circulate in the blood freely and have a lifetime of minutes. Amine hormones, derived from tyrosine, are secreted by the Adrenal Medulla, which makes Epinephrine and Norepinephrine or the thyroid gland, which produces thyroxine and triiodothyronine. Hormone Signalling: Cells can respond to a variety of stimuli such as light, nutrients, developmental signals etc. in terms of hormones, cells respond via receptors. These receptors then act in two distinct functions; Binding; which enables differentiation of one particular hormone from another and signalling, which translates the hormonal signal into an appropriate biological response. These receptors can be membrane bound, which does not allow hormone entry to the cell, instead binding occurs to receptors on the cell surface, which releases a secondary messenger that results in altered activity. Another mechanism are intracellular receptors that allow hormones to bind to receptors in the nucleus, this usually results in the altered transcription of a specific gene and thereby altering the protein produced. This signalling system relies on specificity of the signal molecule to bind to its complementary receptor and that other signal will not. Should enzymes activate enzymes, the number of affected molecules can increase, resulting in enzyme cascade. Polypeptide Hormones: There exists many pathways for the synthesis of various protein hormones, and thereby the various protein hormones results in a variety of actions this hormone class can induce on the body. Some examples are insulin and glucagon, these are produced within the pancreas and modulate CHO metabolism. The hypothalamus releases vasopressin, which modulates renal function and TRH which stimulates the thyroid gland. From the anterior pituitary, LH is released with affects the gonads and GH which affects growth and metabolism. The thyroid gland secretes calcitonin, which affects the bones. They are synthesised via the normal protein synthesis pathway and can be stored in secretory vesicles as prohormones for one day. It release is modulated by hormones, metabolites and the CNS where release is via exocytosis of vesicles. It is transported freely in the blood and only has a lifetime of minutes. It can vary from minutes to hours to act and functions via membrane bound receptors. Inactivation of peptide hormones is via proteolysis. Prohormones can yield more than one type of hormone. They are only activated when required and enzymatic cleavage is very specific. Amine hormones: Amine hormones are tyrosine derived. From the adrenal medulla epinephrine and norepinephrine are synthesised. It follows a simple biochemical pathway. Tyrosine is converted to L- dopa then dopamine to norepinephrine and then epinephrine. Thyroxine (T4) and Triiodthyronine (T3) are produced within the thyroid gland. The synthesis of adrenaline is within the adrenal medulla from tyrosine. It can be stored for several days and secretion is via exocytosis of vesicles, regulated by the CNS, it travels freely in the blood and its lifetime and time of action is in seconds. It responds to cell surface receptors and is inactivated by methylation or conjugation. The synthesis of T4 and T3 is which the thyroid gland from thyroglobulin. It can be stored for several weeks and its secretion is via the proteolysis of thyroglobulin. It is transported in the blood, bound to plasma proteins TGB, transthyretin and albumin. Its lifetime and time of action can last days and it binds to intracellular receptors. Inactivation is caused by conjugation or deamination. Epinephrine (adrenaline) is released in response to stressful stimuli, therefore its method of action is to mobilise energy for a flight or fight response. It increases glycogen breakdown, gluconeogenesis and delivery of oxygen to tissues. It therefore decreases glycogen synthesis. Norepinephrine acts to increase arteriole contraction and lipid release. T4 increase rate of cell metabolism, T3 initiates the same response though is a more biologically active. Steroid Hormones. Steroid hormones are synthesised from cholesterol within the adrenal cortex, testis and ovaries. Cortisol, corticosterone and aldosterone are synthesised within the adrenal cortex and can influence many tissues. The pathway to produce cortisol is initiated by stress factors such as fear, pain and infection. Theses stimuli act on the CNS which stimulate the release of corticotropin releasing hormone from the hypothalamus. This acts on the anterior pituitary which then secretes ACTH (adrenocorticotrophic hormone) which acts further on the adrenal glands to secrete cortisol. This hormone has a variety of induces muscle contraction, glycolysis in the liver and mobilisation of fatty acids from adipose tissue. It also causes negative feedback at the hypothalamus and anterior pituitary. The synthesis of steroid hormones begin with the intake of cholesterol into the steroid producing cells. Many different pathways result in the production of many different steroid hormones, though the main change occurring changes simply the side chain residues and does not affect the ring structure and only alters the shape of the steroid on the outside surface resulting the in the ability to bind to different receptors proteins. Cushing’s syndromes  Occurs due to excess cortisol production  Caused by pituitary or adrenal tumours  Tumours cause increased levels of ATCH or levels of biosynthetic enzyme causing increased steroid levels.  Creates obesity  Rearrangement of fats deposits causing round neck.  Can be driven by chronic steroid use. Cell to cell communication, hormones and signal transduction. Cells communicate with each other via messengers or hormones. How they interact with cells can be divided into two groups either; acting on cell surface receptors and do not enter the cell and initiate intracellular signalling pathways or enter the cell itself and target intracellular receptors. These hormones are lipophilic, which enable entry though the plasma membrane and usually act on nuclear receptors. The hormones themselves are large proteins with very specific recognition sites. They can be membrane bound or intracellular and transmit or relay biological actions. The ability of the cell to respond to a hormone depends entirely on the presence of hormone receptors. Hormone receptors fall into 4 major classes, each class responding and activating to various hormones in different ways. Three out of the four are cell surface receptors, these are; ion channels that are coupled as receptors, G-protien coupled receptors and enzyme linked receptors. Nuclear receptors are intracellular. Ion-channel coupled receptors are located on the plasma membrane and act as a gate of entry to extracellular ions. When a specific hormone is bound to the receptor, these ion channels open and allow for a flow of ion into the cytosol of the cell. G-protien coupled receptors are also membrane bound. They are comprised of an inactive receptor, an inactive G protein and a n inactive enzyme. Binding of the signal molecule to the receptor actives the G protein, which in turn activates the enzyme. Enzyme coupled receptors can act in two ways, two receptors may be found on the cell surface and bind to hormones in dimeric form. They bind and between them create an active catalytic site. Or binding of a single molecule may then in turn activate an associated enzyme. Nuclear receptors are another class of receptors, though are not found on the cell surface, instead they are located intracellularly. When inactivated these receptors consist of a transcription and a DNA-binding domain. It also has a ligand-binding domain coupled with inhibitory proteins. When a ligand binds, inhibitory proteins dissociate to allow coactivator proteins to bind. This alters the shape of the receptor changes and allows for the DNA binding domain to bind to receptor binding elements of the DNA and allow for transcription. Hormone Receptors One example of a hormone receptor is the human epidermal growth factor receptor 2 (HER2). It regular function is to provide signals that initiate cellular proliferation. It is a tightly regulated process, that when compromised has been shown to greatly contribute to caners, in particular breast cancer. It is over expressed in 40% of breast cancers, and is seen to increase and promote cell proliferation. It usually accompanies a bad prognostic outcome. Herceptin, a humanised monoclonal antibody, is a drug that has been developed to specifically target HER2 receptors and block their action. Hormones that act on membrane bound receptors do not directly induce transcription as those that act on intracellular receptors do. Instead they initiate a cascade of intracellular reactions and rely on secondary messengers that, after a series of various intracellular reactions, ultimately result in transcription. The main intracellular mechanisms that take place after ligand binding are the activation of these secondary messengers, which then cause enzyme modification. Secondary messengers These secondary messengers occur intracellular and are released by the binding of hormones to the membrane bound receptors. One example is cAMP, this acts as a secondary messenger for various hormones such as glucagon, epinephrine, LH, FSH, TSH, PTH and CRH. It acts by binding to other inactive proteins and activating them to further act in the hormone cascade. For example, should a hormone activate a membrane bound, G-protein coupled receptor, ATP is used and converted into cyclic AMP. This binds to inactive protein kinase a receptors, releasing activated PKA. PKA is able to move into the nucleus, where it can activate cAMP response element binding protiens (CREB) that are transcription factors that bind to regions on the DNA to
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