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With Particular emphasis on the specific molecular interactions of phytochemicals, discuss the means by which mammalian chemical signals are coupled to elicit cellular responses.
Homeostasis is deriverd from the Greek words: homios ( like, same, resembling ) and stasis (posture, to stand ) is the maintenance of constancy of human's internal environment ( and all mammals ). A number of organs within the body must be coordinated to achieve homeostasis via interaction and feedback control mechanisms. Cells within the body liberate signal molecules to communicate ( e.g hormones and neurotransmitters) to maintain the homeostatic balance. Signal molecules start their actions by binding to proteins called receptors.
The phytochemicals contained within certain classes of plants, especially the products of secondary metabolism often chemically resemble human endogenous signalling molecules. These phytochemicals can affect the way chemical signals within the human body respond, acting as antagonists ( which bind to receptors, blocking a response ) or agonists ( which can trigger a response ). The specific ligand, the type of receptor that is acted upon, type of cell and the interacellular signalling mediators involved determines the type of response produced.
Most receptors are proteins and can be divided in to four superfamilies. These are: G-protein coupled receptors, steroid receptors, iontropic ion channel receptors and receptor Tyrosine Kinases ( TK ).
G- protein receptors ( Guanine nucleotide binding proteins, also known as seven transmembrane receptors, as they span the cell plasma membrane seven times ) are the most common receptor type , they evoke cellular responses as part of a fast acting signalling system. Each G protein is made up of a specific type of alpha sub unit which responds to specific hormones or neurotransmitters ( first signal ), and beta/gamma units. The hydrophillic extracellular part of the G protein binds to the signal molecule ( hormones or phytochemical ), this causes a change in the shape of the receptor, and a reduced attraction of the alpha subunit for it is bound Guanosine Diphosphate ( GDP ), which gets released and then replaced by Guanosine Triphosphate ( GTP ). The alpha subunit separates and diffuses through the membrane to a targetted protein.
The alpha and the beta/gamma subunits can then move freely along the membrane surface and activate the effector the enzyme adenylate cyclase, this will catalyse the formation of cyclic adenosine monophosphate ( cAMP ) molecules that act as second messengers carrying the signal and activate their targets which are no longer confined to the cell membrane. cAMP-phosphodiesterase converts cAMP continuously in to non cyclic AMP. Protein kinase A is activated by cAMP binding to it , which catalyses the phosphorolation of other enzymes or target proteins Phospholoration activates some of these proteins and inactivates others a bit like a switch. The final target protein within the cell is functional, with a specific response e.g glycogen synthesis or breakdown of a triglyceride. Unless G-proteins are further stimulated by binding of a hormone at the receptor site phosphodiesterase inactivates cAMP and the cells response is turned off.
Other second messengers include cyclic guanosine monophosphate ( cGMP ), inositol trisphosphate ( IP3 ) which can raise intracellular calcium levels, diacylglycerol ( DAG ) which activates Protein Kinase C ( PKC ) and calcium ions ( Ca2+ ). Nitric oxide activates guanylyl cyclase, this enzyme converts guanosine triphosphate ( GTP ) to cGMP. This causes calcium ions to enter storage areas of smooth muscle fibres and as a result this causes muscle relaxation.
Platelet Activating factor ( PAF ) is an ether lipid signalling molecule, with effects many body systems and is particularly important in the cellular immune response. PAF stimulates platelet aggregation and the release of serotonin from the platelets and is important in haemostasis. It is produced and released from basophils, endothelial cells, eosinophils, macrophages, neutrophils, lymphocytes, monocytes and mast cells, which also respond to PAF. It is important in inflamation and immune responses ( Nelson 2005 ). Development of respiratory and cardiovascular disorders, allergic response, anphylactic shock and hypertension is connected with platelet actions. PAF's actions can be antagonised by a number of phytochemicals, which block the G-protein coupled receptor with which it binds. Examples include Ginkgolides found in Gingko Biloba and Ligans and neoligans which include Kadsurenone found in Piper futukadsura. ( Furukawa, 1997 )
Steroid receptors are intracellular proteins found in the cytoplasm or nucleus of a cell which bind to and regulate the transcription of DNA under the regulation of the hydrophobic steroid hormones, via their zinc finger domain. As opposed to the G-protein receptors this is generally a slow signalling system. Receptors for the different hormones have strong structural and functional similarities which point to an evolution from a common ancestral gene ( Fox 2004 ).The binding between flavanoid phytoestrogens and oestrogen receptors, and both their ability to compete with endogenous oestrogen for binding of their receptors and also the activation of oestrogen-responsive genes acting as weak agonists has been the focus of much research. This may have therapeutic implications in the prevention and treatment of breast cancer ( ref hoffmann book )
The steroid hormone receptors can be divided in to three functionally distinct subfamilies, these are: Type I, classical steroid hormone receptors including the glucocorticoid ( GR ), androgen ( AR ), mineralcorticoid ( MR) and progesterone receptor, Type II consists of thyroid hormone related receptors which include RAR, RXR , T3R and VDR and Type III is formed by the eostrogren ( ER)receptor and a few 'orphan receptors'.
Ionotropic ion channel recptors