Essential Endocrinology and Diabetes. Richard I. G. Holt
alt="c02i001"/> Key points
Mutations in DNA and chromosomal abnormalities can cause endocrine disease
Meiosis is central to reproductive endocrinology
Peptides and proteins are encoded by genes, which are stretches of genomic DNA
Many protein hormones are synthesized as prohormones, which require post‐translational modification and processing before they become active
Enzyme cascades synthesize hormones derived from amino acids and cholesterol
Unlike peptide hormones, steroid hormones are not stored in cells but made on demand
Many peptide hormones circulate free in the blood, unlike steroid or thyroid hormones, which associate with binding proteins
CHAPTER 3 Molecular basis of hormone action
Key topics
Learning objectives
To understand the principles of hormone–receptor interaction
To know the different classes of hormone receptors and how they functionTyrosine kinase receptors and their signalling pathwaysG‐protein–coupled receptors and their signalling pathwaysNuclear receptors and how they regulate gene expression
To appreciate the role of transcription factors that are important in endocrine development and function
To appreciate how abnormalities in hormone receptors or their downstream signalling can cause endocrinopathy
This chapter describes the key events that occur within the cell following stimulation by hormone
Hormones act by binding to receptors. There are two superfamilies of hormone receptor: the cell‐surface receptors and the nuclear receptors, named according to their site of action. Both classes display characteristic features (Figure 3.1 and Box 3.1).
Cell‐surface receptors
Cell‐surface receptors comprise three basic components (Figure 3.2). Signalling through the receptors is initiated by binding of the hormone to the receptor followed by signal transduction.
Binding of hormone to receptor
Historical experiments used radiolabelled hormones and isolated preparations of receptors to define two properties of binding (Box 3.2). The hormone–receptor interaction is both saturable (Figure 3.3) and reversible (Figure 3.4).
Using methodology similar to that for immunoassays (Chapter 4), constant amounts of labelled hormone and receptor preparations can be incubated with increasing, known amounts of unlabelled hormone for a specified time. Separating and measuring the receptor‐bound, labelled fraction allows curves to be plotted and mathematical modelling of the hormone (H)–receptor (R) interaction; e.g. whether it conforms to the equation H + R ⇆ HR. These types of experiment can also allow estimation of the number of hormone receptors present on each target cell.
Signal transduction
When a hormone binds to a cell‐surface receptor, two major types of signalling cascade unfold inside the cell; protein phosphorylation by kinase enzymes or the generation of ‘second messengers’ via coupling to guanine (‘G’) proteins. Signalling through either process amplifies the hormone response as many protein phosphorylation events or second messenger molecules are produced for each hormone–receptor interaction. These two types of signalling pathway divide the cell‐surface receptor superfamily into two subclasses: tyrosine kinase receptors and G‐protein–coupled receptors (GPCRs) (Figure 3.1 and Box 3.3).
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