IPHY 4440 1st Edition Lecture 9 Outline of Last Lecture I. ReceptorsOutline of Current Lecture II. Kinases III. Nuclear receptor familyIV. Alternative nomenclature since both receptors can bind glucocorticoids V. Thyroid receptors Current LectureI. KinasesA. Phosphorylating enzymes: tyrosine kinases, serine kinases B. Receptors may be ion channels: can depolarize/hyperpolarize, can allow Ca2+ influx, Ca2+ can be a second messenger C. Cross talk: one messenger can affect another messenger via common intracellular pathways (Just know that they do occur along these pathways)II. Nuclear receptor familyA. Over 300 members identified, they are all transcription factors- Most ligands are unknown: orphan receptors B. Transcription factors: orphans, no known ligand. - Ligand activated: has known ligand = ligand activated transcription factors (LATFs)C. Examples:- Orphans: Aryl hydrocarbon receptor (AhR) or SF-1 receptor- LATFs: Steroid receptors, Thyroid receptors, Retinoic acid receptor, 1, 25 dihydroxy Vitamin D3 receptor D. Steroid receptors: Estrogen receptors (ER): Era, ERb (different affinities for various ligands) E1, E2, E3 are promiscuous SERMs  Phthalates, BPA, Nonylphenol, Pesticides, Phytoestrogens, etc. Androgen receptors (AR): two isoforms, A & B. Greatest affinity DHT > T > AND > DHEACorticoid receptors (GR & MR): glucocorticoid receptor (GR) binds only coritcosterone or cortisol Progesterone receptors (PR): mineralocorticoid receptor (MR) B, F > aldosteroneThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- two forms: PR-A & PR-B, progesterone is most common progestogen ligand MR binds to both glucocorticoids as well as mineralocorticoids with greater affinity to B,F then Aldo III. Alternative nomenclature since both receptors can bind glucocorticoids Type 1 GR: GR-1 binds B, F > aldosterone = MRType 2 GR: GR-2 binds B & F only = GRSo glucocorticoids can activate both GR and MRIV. Thyroid receptorsTRa, TRB1, TRB2A. Retinoic acid receptor: RAR & RXR (retinoic X receptor, orphan)- Both can dimerize V. Aryl hydrocarbon receptor (AhR)- It is an orphan because no naturally occurring ligand that we produce to bind AhR so binds to things external- Environmental contaminants (PCBs, dioxins) - Bind to external contaminants - This particular receptor has evolved as an environmental sensor - Good enzymes from liver - No endogenous ligand A. SF-1 receptor: steroidogenic factor-1, orphan, no ligand, important transcription factor, numerous roles including sexual differentiation B. Nuclear receptors: are found intracellularly, some are cytosolic (CR), some occur in nucleus (ER, TR), some are in cytosol in one cell type and in nucleus of another (AR, PR)C. Structure of nuclear receptors domains:- ligand binding (LBD), DNA binding (DBD), dimerizationClicker: what is the 2nd messenger in the MAP kinase pathway?a) Phosphate (always there)b) Dimerized receptor (receptors cannot be second messengers) c) Adapter proteins (always there in the cell, not produced from scratch, just being modified) d) MAP kinase (enzyme, always there just needs to be activated) e) None CORRECT*** (Second messenger system is none in this system) If you have a receptor that is functional like tyrosine kinase (has room) does not need second messengers When receptor itself is not functional: need second messengerCan amplification exist without no second messengers? Yes if there is phosphorylation occurringMost of the signaling pathways we talk about there are amplifications Thought question: Hormone A is important for reproduction (have to have it or will go sterile)You make hormone A agonist with long half life and inject into an organism, hoping to enhance reproduction…Instead you sterilize the organism, why?Comments: Provide negative feedback to something that is controlled by hormone A because so powerful, down-regulation shut down Endocytosis of the membrane receptors: