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Figure 3.1 The different classes of hormone receptor. Some cell‐surface receptors, e.g. the parathyroid hormone (PTH) receptor, can link to different G‐proteins, which couple to either adenylate cyclase or phospholipase C (PLC). TK, tyrosine kinase; TRH, thyrotrophin‐releasing hormone; GnRH, gonadotrophin‐releasing hormone; TSH, thyroid‐stimulating hormone; LH, luteinizing hormone; FSH, follicle‐stimulating hormone; ACTH, adrenocorticotrophic hormone; PTHrP, parathyroid hormone‐related peptide; PGE2, prostaglandin E2; GHRH, growth hormone‐releasing hormone; IGF‐I, insulin‐like growth factor I.
Box 3.1 Some basic facts about hormone receptors
Tissue distribution of receptor dictates the scope of hormone action:The thyroid‐stimulating hormone (TSH) receptor is expressed almost exclusively in the thyroid, therefore TSH action is largely restricted to the thyroidThyroid hormone receptor expression is widespread and therefore thyroid hormone action is diverse
Binding of hormone induces conformational changes in the receptor to initiate downstream signalling
Downstream signalling can differ across different cell‐types to produce diverse hormone‐mediated effects
Control is exerted in part through the ongoing synthesis, degradation and localization of hormone receptors – most target cells have 2000–100,000 receptors for a particular hormone
Cell surface hormone receptors
Bind water‐soluble hormones (e.g. peptides):
Transduce signal through membrane (that is otherwise impermeable to water‐soluble hormones)
Activate intracellular signalling pathways
Fast responses (seconds) possible
Nuclear hormone receptors
Bind lipid‐soluble hormones (e.g. steroid and thyroid hormones) which can pass through cell membranesFunction as transcription factors in the nucleusActivate or repress gene expression
Relatively slow responses (hours)
Figure 3.2 Basic components of a membrane‐spanning cell‐surface receptor. The hormone acts as ligand. The ligand‐binding pocket in the extracellular domain tends to be comparatively rich in cysteine residues that form internal disulphide bonds as part of a precise three‐dimensional folded structure. For some hormones, e.g. growth hormone, the extracellular domain can be cleaved and circulate as a potential binding protein. Circulating fragments of the thyroid‐stimulating hormone receptor can be immunogenic leading to auto‐antibody formation in autoimmune thyroid disease. The α‐helical membrane‐spanning domain is rich in hydrophobic and uncharged amino acids. The C‐terminal cytoplasmic domain either contains, or links to, catalytic sites, which initiate intracellular signalling stimulated by hormone binding.
Box 3.2 Binding characteristics of hormone receptors
High affinity: hormones circulate at relatively low concentrations – receptors are like ‘capture systems’
Reversible binding: one reason for the transient nature of endocrine responses
Specificity: receptors distinguish between closely related molecular structures
Protein phosphorylation is a key molecular switch. Approximately 10% of proteins are phosphorylated at any given time in a mammalian cell. The phosphate group is donated from ATP during catalysis by the kinase enzyme. It is accepted by the polar hydroxyl group of the amino acids, serine, threonine or tyrosine (Figure 3.5a) and causes a conformational change in the three‐dimensional shape of the protein (Figure 3.5b). In many signalling cascades, the phosphorylated protein can also act as a kinase and phosphorylate the next protein in the sequence. This relays and amplifies the intracellular signal generated by the hormone binding to its receptor (Figure 3.5c).
Figure 3.3 Hormone–receptor systems are saturable. Increasing amounts of labelled hormone are incubated with a constant amount of receptor. The amount of bound labelled hormone increases as more is added until the system is saturated. At this point, further addition of hormone fails to increase the amount bound to receptors. The concentration of hormone that is required for half‐maximal saturation of the receptors is equal to the dissociation constant (K D) of the hormone–receptor interaction.
Figure 3.4 Hormone–receptor interactions are reversible. Constant amounts of labelled hormone and receptors are incubated together for different times. The bound label increases with time until it reaches a plateau, when the bound and free hormone has reached a dynamic equilibrium. In a dynamic equilibrium, hormone continually associates and dissociates from its receptor. Adding excess unlabelled hormone competes for access to the receptors. Consequently, the amount of bound labelled hormone decreases with extended incubation (dashed line).
Box 3.3 Categories of cell‐surface receptors
Tyrosine kinase receptors
Signal via phosphorylation of the amino acid, tyrosine
G‐protein–coupled receptors
Activate or inhibit adenylate cyclase and/or phospholipase C (PLC)
Signal via second messengers: cyclic adenosine monophosphate (cAMP), inositol triphosphate
