SERPENTINE RECEPTOR Receptor contains 7 transmembrane alpha-helical segments & intracellular and extracelullardomains ADENYL CYCLASE camp Enzyme contains about1100 aminoacids, two clusters of six transmembrane segments separatingtwo similar cytoplasmic catalytic domains. There are atleast six types of this form of adenylyl cyclase in in mammals (types I-VI). TWO PRINCIPAL SIGNALLING PATHWAYS cgmp
RECEPTORS Cell surface receptors without enzymatic activity Ion channel linked GPCR with enzymatic activity Guanyl cyclase Tyr- kinase Ser/Thr -kinase Ser/Thr -phosphatase Binding of secreted signals to receptors Intracellular receptors cytoplasmatic receptors nuclear receptors Cell surface receptors Ligand binds directlyto ion channel Specialreceptor coupledto G protein cascade Receptor with intrinsic enzyme activity
Some Hormone-induced Cellular Responses Mediated by Cyclic AMP Hormone Target Tissue Major Response Thyroid-stimulating hormone (TSH) Thyroid gland thyroid hormone synthesis and secretion Adrenocorticotropic hormone Adrenal cortex cortisol secretion (ACTH) Luteinizing hormone (LH) Ovary progesterone secretion Adrenaline Muscle glycogen breakdown Noradrenalin, Adrenaline Heart increase in heart rate and force of contraction Parathormone Bone bone resorption Glucagon Liver glycogen breakdown Vasopressin Kidney water resorption Adrenaline, ACTH, glucagon, TSH Fat triglyceride breakdown Some Cellular Responses Mediated by G-Protein-linked Receptors Coupled to the Inositol-Phospholipid Signaling Pathway Signaling Molecule Target Tissue Major Response Vasopressin Liver glycogen breakdown Acetylcholine Pancreas amylase secretion Acetylcholine Smooth muscle contraction Antigen Mast cells histamine secretion Thrombin Blood platelets thrombin Endocrine disorders associated with mutation of serpentine receptors Mutated protein Disorder Type of mutation Gain of function LH receptors Familiar male prococious puberty Autosomal dominant TSH receptor Non-autoimmune hereditary hyperthyroidism Hyperfuncioning thyroid adenoma Autosomal dominant Somatic PTH receptor Jansen metaphysal chondrodysplasia Autosomal dominant Calcium receptor Hypoparathyroidism Autosomal dominant Loss of function LH receptor Male pseudohermafroditism Autosomal recessive FSH rceptor Hypergonadotrophic ovarian Autosomal recessive dysgenesis GHRH Laron dwarfism Autosomal recessive TSH receptor Congenital hypothyroidism Autosomal recessive TRH receptor Congenital hypothyroidism Autosomal recessive ACTH Familial ACTH resistance Autosomal recessive Vasopressin Nephrogenic diabetes insipidus X-linked Calcium receptor Familial hypocalciuric hypercalcaemia Neonatal severe hyperparathyroidism Autosomal dominant Autosomal recessive
INOSITOL-PHOSPHATE DEPENDENT SIGNALLING Substance Receptor Transduction Acetylcholin M 1,M 3,M 5 Catechoamines fi α 1A,1B,1C,1D Serotonin fi 5-HT 2A,2B,2C Histamin fi H 1 Adenosin fi A 1,A 3 Purines fi P 2U,P 2Y EAMA fi mglu 1,mGlu 5 Vasopressin fi V 1A,V 1B Oxytocin fi Oxy G q/11 fi æ IP3/DAG Cholecystokinin fi CCK A,CCK B Melanin fi ML 2 Angiotensin fi AT 1 Bradykinin fi B 1,B 2 Tachykinins fi NK 1,NK 2,NK 3 Bombesin fi BB 1,BB 2 Endothelin fi ET A,ET B,ET C Prostanoids fi EP 1 Leukotriens fi LTB 4,LTD 4 PAF fi PAFR
c-amp DEPENDENT SIGNALLING Substance Receptor Transduction Catecholamines fi β1,2,3 Serotonin fi 5-HT 4,5,6,7 Dopamin fi D1(D1A),D5(D1B) Histamin fi H 2 Adenosinn fi A2A,A2B Vasopressin fi V2 Gs fi æ camp VIP fi VIP 1,2,GRF Prostanoidy fi EP2,EP4 Octopamin fi OA 2A,OA 3 CGRP fi CGRPR Substance Receptor Transduction Acetylcholin fi M 2,M 4 Catecholamines fi α2a,2b,2c,2d Serotonin fi 5-HT 1A,1B,1D,1E,1F Dopamin fi D 2,D 3,D 4 GABA fi GABA B, Adenosinn fi A 1,A 3 Purines fi P1, P2T EAMK fi mglu 2,3,4,6,7,8 Opioides fi µ,δ,κ Somatostatin fi SST 2,3,4 Melanin fi ML 1A,1B Intereleukines fi IL8 A,IL8 B Chemokines fi CCCK 1,2,3 Protease fi PAR1 NPY fi Y 1,Y 2,Y 3 Galanin fi Gal Prostanoids fi EP 3 Gi/o fi camp
PRINCIPLE OF AMPLIFICATION PRINCIPLE OF INTEGRATION
INOSITOL PHOSPHOLIPIDS (PHOSPHOINOSITIDES) PIP2 HYDROLYSIS PIP2 C-KINASE ACTIVATED GENE TRANSCRIPTION
Same ligand can bind to different receptors ACh ACh(N) ACh(M) 1 ACh(M) 2 ACh(M) 3 ACh(M) 4 ACh(M) 5 R R R R R Gq Gi PLC AC Gq PLC Gi AC Gq PLC Na/K/Ca + + 2+ IP3/DAG camp IP3/DAG camp IP3/DAG +Nikotín +McN-A-343 +Oxotremorín-M +Oxotremorín-M +Oxotremorín-M +Oxotremorin-M α Anatoxin Oxotremorín-M Epibatín Epiboxidín -Neosurugatoxín -Pirenzepín -Metoktramín -Hexahydrozyl -Himbacín α -Bungarotoxín Telenzepín Gallamín Odifenidol Tropicamid α -Kobratoxín QNXhemioxalát Himbacín 4-DAMP Atropín α -Konotoxín Atropín 3α -Cl-Imperialín Atropín Skopolamín Tubokurarín Skopolamín Atropín Skopolamín Dekametónium Skopolamín Hexametónium Metyllykatónium Gallamín Different Cells Can Respond Differently to the Same Chemical Signal