Peptide hormone signal transduction and regulation
- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
Signal transduction is a process by which a peptide hormone transfers specific information from the outside of the target cell to elicit a cellular response. For this to occur, the hormone (eg, secretin) exerts a signal through a specific receptor that transmits information from the extracellular compartment (eg, blood) into the cell. For example, in the gastrointestinal tract, secretin is released from cells in the duodenum and is taken by the blood to the pancreas, where it binds specific receptors on duct cells. Secretin binding to its receptor initiates a signaling cascade that generates the second messenger, cyclic adenosine monophosphate (cAMP), resulting in secretion of fluid rich in bicarbonate. The transfer of information from the outside to the inside of the cells is tightly controlled, especially in settings that are vital for cellular homeostasis.
The normal function of a cell depends upon an intact signal regulation/termination system. If this system malfunctions, the host may experience pathophysiologic consequences, such as abnormal secretion, motility, growth, or even the development of cancer [1,2].
There are three major categories of cell-surface peptide receptors that are based on their structure and signaling mechanisms. These include G protein-coupled receptors (GPCRs), enzyme-coupled receptors, and ion channel-coupled receptors.
The major physiologic principles of cell signaling systems will be reviewed here. Discussions of individual peptide hormones are presented separately. (See "Overview of gastrointestinal peptides in health and disease" and "Physiology of cholecystokinin" and "Physiology of gastrin".)
Despite the vast array of information communicated to a cell, the basic components of the signaling system are relatively simple (figure 1). A peptide hormone binds to a cell-surface receptor and stimulates activation of an effector system. Cell-surface receptors are capable of interacting with only certain chemical messages. The specificity of the hormone-receptor interaction is responsible for the unique cellular response.
- Lefkowitz RJ. G proteins in medicine. N Engl J Med 1995; 332:186.
- Krontiris TG. Oncogenes. N Engl J Med 1995; 333:303.
- Vaughan M. Signaling by heterotrimeric G proteins minireview series. J Biol Chem 1998; 273:667.
- Neer EJ. Heterotrimeric G proteins: organizers of transmembrane signals. Cell 1995; 80:249.
- Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002; 3:639.
- Mason JS, Bortolato A, Congreve M, Marshall FH. New insights from structural biology into the druggability of G protein-coupled receptors. Trends Pharmacol Sci 2012; 33:249.
- Krupnick JG, Benovic JL. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu Rev Pharmacol Toxicol 1998; 38:289.
- Ranganathan R, Stevens CF. Arrestin binding determines the rate of inactivation of the G protein-coupled receptor rhodopsin in vivo. Cell 1995; 81:841.
- Ferguson SS, Downey WE 3rd, Colapietro AM, et al. Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 1996; 271:363.
- Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science 2005; 308:512.
- Ibrahim IA, Kurose H. β-arrestin-mediated signaling improves the efficacy of therapeutics. J Pharmacol Sci 2012; 118:408.
- Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103:211.
- Pawson T. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 2004; 116:191.
- Simon MA. Receptor tyrosine kinases: specific outcomes from general signals. Cell 2000; 103:13.
- Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113:685.
- Burgoyne RD, Haynes LP. Sense and specificity in neuronal calcium signalling. Biochim Biophys Acta 2015; 1853:1921.
- Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest 2010; 120:3760.
- Wellendorph P, Johansen LD, Bräuner-Osborne H. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients. Mol Pharmacol 2009; 76:453.
- Reimann F, Tolhurst G, Gribble FM. G-protein-coupled receptors in intestinal chemosensation. Cell Metab 2012; 15:421.
- Wauson EM, Lorente-Rodríguez A, Cobb MH. Minireview: Nutrient sensing by G protein-coupled receptors. Mol Endocrinol 2013; 27:1188.
- Farfel Z, Bourne HR, Iiri T. The expanding spectrum of G protein diseases. N Engl J Med 1999; 340:1012.
- Schöneberg T, Schulz A, Biebermann H, et al. Mutant G-protein-coupled receptors as a cause of human diseases. Pharmacol Ther 2004; 104:173.
- Vassart G, Costagliola S. G protein-coupled receptors: mutations and endocrine diseases. Nat Rev Endocrinol 2011; 7:362.
- Parma J, Duprez L, Van Sande J, et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993; 365:649.
- Shenker A, Laue L, Kosugi S, et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993; 365:652.
- Ringel MD, Schwindinger WF, Levine MA. Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. Medicine (Baltimore) 1996; 75:171.
- Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325:1688.
- Shenker A, Weinstein LS, Moran A, et al. Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS. J Pediatr 1993; 123:509.
- RECEPTOR STIMULATION
- G proteins
- G protein-coupled receptors
- Effector systems
- - Adenylate cyclase
- - Phospholipase C
- SIGNAL REGULATION AND TERMINATION
- - Beta-arrestin
- Enzyme-coupled receptors
- - Receptor tyrosine kinases
- - Receptor serine/threonine kinases
- Ion channel-coupled receptors
- PHYSIOLOGIC NUTRIENT SENSING
- PATHOPHYSIOLOGIC RELEVANCE