Previously Previously in Cell Bio Today A) Fluid Mosaic Model B) Cell Parts: Components and Organelles C) Introduction to first case study Graves’ disease/ hyperthyroidism Today Signaling its roles in Graves’ disease

Thyroid activators How are they all coordinated? Our Case Study  Thyroid stimulation: Extracellular signaling and the receptors that mediate it ‘Activating’ Signals: Hypothalmus: Thyrotropin releasing hormone (TRH) Pituitary Gland Thyroid stimulating hormone (TSH) Thyroid T4 (thyroxine) T3 (triiodothyronine)

Signaling types Types of Extracellular Signaling Up close Direct contact PM receptors Gap junctions Secreted ECM Autocrine Through space Paracrine Endocrine Synaptic

What types in thyroid regulation? Normal thyroid function What types in thyroid regulation? Endocrine signaling: (Intracellular receptor for T4) Endocrine signaling PM receptor Negative feedback loop: What is it and why is it important?

Binding vs. Effector Specificity Symptoms in Graves’ Disease Increase in circulating thyroid hormone causes: Increase in secretion by sweat glands Increase in rate and force of heart contractions Decrease in muscle strength How can this happen?

Binding vs. effector specificity 2 How can thyroid hormone cause different responses in different parts of the body? Ligand needs to bind with receptor Different cells make different receptors Same receptor/ligand complex may trigger different response in a different cell type Differences between binding specificity and effector specificity (Receptors and Ligands? What are they?)

Receptor characteristics Characteristics of a receptor: What does it need to have to do its job? Ribbon diagram of Thyroid hormone bound to Thyroid hormone receptor Diagram of isoproterenol bound to B2 adrengergic receptor (Fig20-1 Molecular Cell Biology)

Types Types of Receptors G-protein linked receptors (G protein coupled receptors/GPCR) Ion Channel receptors Enzyme linked receptors (Receptor S/T kinases, Receptor Y kinases Receptor guanylyl cyclases, Protein Y phosphatases, Y-kinase associated receptors H-kinase associated receptors) Intracellular receptors

What happens in Graves’? What’s different in a Grave’s disease patient? (hyperthyroidism=increased thyroid function) What happens in Graves’? Patients have increased T3 and T4 in bloodstream What might make a thyroid put in overtime? HYPOTHESES?

Hypothesis : Thyroid being over-stimulated Normal stimulation results from TSH/receptor interaction How does the thyroid know to react? How does a receptor provide specificity Hypothesis: Mutation in signaling within cell leading increase in thyroid hormone production Normal activation is the result of signal transduction second messenger cascade How does signal transduction work? What could have gone wrong?

Testing the hypotheses IF hypothesis is true then what is expected? What data would suggest the hypothesis needs to be revised? Tonight: Research Symposium Tomorrow: 2pm Dr Mimms seminar Next week: Lecture: How ‘normal’ signals get in Lab: Analysis of complementation How much mating is ‘normal’ (‘productive’ response to signal)