Extracellular messengers that elicits a cellular response when it binds to a Learning Objectives Number 4 Ocean See the review sheet on Moodle Cell Signaling What are first messengers receptor protein Hormones neurotransmitters What are two examples of second messengers cAMP cyclic adenosine monophosphate o Synthesized from ATP o Activates an enzyme called protein kinase Calcium o Muscle contractions Amplify faint signal What is signal amplification and how does it benefit the cell o A few first messenger molecules o Many second messenger molecules o Each step in the cascade recruits more molecules Elicit a coordinated response What is the role of phosphorylation cascades in signal amplification Activated kinase activates a different kinase At each step more enzymes are recruited Where are the receptors involved in cell signaling located May involve a receptor in the plasma membrane o An integral membrane protein May involve an intracellular receptor o Steroid hormone receptors Signal amplification in the breakdown of glycogen Epinephrine adrenaline activates a GPCR in liver cells Calcium activates a phosphorylation cascade in skeletal muscle after the Protein Kinase A step in Fig 11 16 activating the enzyme phosphorylase kinase The relationship of adenylyl cyclase and cAMP Adenylyl cyclase produces cAMP How is adenylyl cyclase activity regulated The enzyme is modulated positively and negatively by different G proteins Intracellular cAMP levels go up or down o Depends on the summation of all the positive and negative signals on that cell What reactions do protein kinases and phosphatases catalyze 1 Protein kinases phosphorylation reactions o Covalent transfer of phosphate group from ATP to specific amino acids of target proteins o Acts as an on or off switch for the target protein Phosphates remove phosphate groups What is the role of cAMP dependent Protein Kinase Protein Kinase A in cell signaling Catalyze phosphorylation reactions What are the subunits of Protein Kinase A and what do they do Two regulatory subunits Two catalytic subunits What is the subunit composition of the active enzyme In the cytoplasm cAMP binds to the R subunit R2C2 dissociates into an R dimer and 2 C monomers C monomers catalyze phosphorylation reactions Of the inactive enzyme R2C2 G proteins What is G protein cycle Be sure you know all of the steps in the cycle and can reproduce it from memory o Switch proteins o Either on or off o Activated by occupied activated receptor o GDP is bound to the alpha subunit of the inactive G protein heterotrimer o Inactive off alpha GDP beta gamma o Active on alpha GTP beta gamma Alpha subunit with GTP bound and a beta gamma dimer Activation of G proteins o An activated receptor interacts with the G protein o GTP replaces GDP on the alpha subunit o The G protein dissociates into alpha GDP and a beta gamma dimer o The G protein is now on Activated G protein subunits o Interact with their target enzymes or ion channels Inactivating G proteins o Turned off when an intrinsic GTPase activity of the alpha subunit hydrolyzes GTP to GDO o Alpha GDP and the beta gamma dimer re associate G protein coupled signaling o Membrane receptor is activated by an extracellular signal o G protein transfers the extracellular signal into the intracellular compartment by interacting with a target o Target enzyme produces an intracellular second messenger What are examples of the types of G proteins 2 GS stimulatory G protein GI Inhibitory G protein o Inhibits adenylyl cyclase Golf olfactory G protein GT transducing the G protein involved in vision What are the subunits of G proteins Alpha Beta and Gamma Inhibitory and stimulatory signals and receptors What would happen if the G protein cycle were disrupted by mutations Loss of function mutations prevent formation of stable mRNA or protein Gain of function mutations activation of receptor in the absence of agonist See Potential Targets for Disease on Moodle See the G protein cycle sheet and the work sheet on Moodle figures 11 5 11 6 11 7 11 9 11 10 11 11 11 12 11 15 and 11 16 Hormones What is homeostasis Steady state physiological condition Constancy of the interior environment of an organism What are examples of homeostasis Constant intracellular pH Body temperature Ion concentrations What is meant by antagonistic Hormones that work against each other What is feedback regulation Fig 45 17 End product of a pathway inhibits an enzyme in the pathway What is the endocrine system Regulatory system that maintains homeostasis through hormones Consists of hormones and the glands endocrine glands ductless glands which secrete them How are hormones transported to their targets Endocrine glands secrete hormones into the bloodstream What makes a cell a target for a particular hormone Have receptors for specific first messengers Different cell types will have a different profile of receptors The regulation of blood glucose concentrations What are the three hormones directly involved What do these three hormones do Insulin Glucagon Osteocalcin o Lowers blood glucose level o Raises blood glucose levels o Makes beta cells in pancreas extra insulin What chemical class do these hormones belong to 3 Peptide hormones Where are these hormones produced Insulin and glucagon o In the pancreas Osteocalcin o In the skeleton Know the two types of diabetes discussed in lecture What are the underlying causes Type 1 Type 2 o Autoimmune destruction of cells releasing insulin Inability to produce insulin o Onset related to obesity Failure of the signal transduction system to elicit a response to insulin or inadequate insulin production The regulation of blood calcium levels What are the hormones involved in blood calcium regulation Where are these hormones produced Calcitonin produced in the thyroid gland Parathyroid Hormone PTH produced in the parathyroid gland What is osteoporosis and what might cause it Age related alteration in bone homeostasis Can also result from glucocorticoid administration Estrogens important in prevention of postmenopausal osteoporosis o Thought to act by opposing the calcium mobilizing bone reabsorbing effect of PTH What are examples of steroid hormones Glucocorticosteriods cortisol Mineralocorticoids aldosterone Androgens testosterone Where are the receptors for steroid hormones found What are examples of hormones that bind to intracellular receptors Intracellular receptors Lipid soluble hormones What is the role of hormone cascade Fig 45 17
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