Mechanisms of Hormone Action

Prepared by: Endale Hadgu

Hormone Receptors
Hormones are present at very low concentrations in the extracellular fluid, generally in the atto- to nanomolar range (1015 to 109 mol/L). This concentration is much lower than that of the many structurally similar molecules (sterols, amino acids, peptides, proteins) and other molecules that circulate at concentrations in the micro- to millimolar (106 to 103 mol/L) range. Target cells, therefore, must distinguish not only between different hormones present in small amounts but also between a given hormone and the 106- to 109-fold excess of other similar molecules.

 This high degree of discrimination is provided by cell-associated recognition molecules called receptors. Cells respond to a hormone when they express a specific receptor for that hormone. The hormone binds to the receptor resulting in the activation of a signal transduction mechanism that ultimately leads to cell type-specific responses. Receptor numbers and type vary greatly in different target tissues, providing one of the major determinants of specific cellular responses to circulating hormones.

 For example, ACTH receptors are located almost exclusively in the adrenal cortex, and FSH receptors are found only in the gonads. In contrast, insulin and TRs are widely distributed, reflecting the need for metabolic responses in all tissues.

 Receptors for hormones are divided into two major classes: membrane and nuclear Membrane receptors primarily bind peptide hormones and catecholamines. Nuclear receptors bind small molecules that can diffuse across the cell membrane, such as TH, steroids, and vitamin D.

Cell-surface receptor proteins (Membrane Receptors) and Mechanism of Action Proteins, peptides, catecholamines and eicosanoids initiate a response by binding to a receptor located in the plasma membrane The mechanism of action of this group of hormones can best be discussed in terms of the intracellular signals they generate. These signals include cAMP (cyclic AMP; a nucleotide derived from ATP through the action of adenyl cyclase; cGMP, a nucleotide formed by guanylyl cyclase; Ca2+; and phosphatidylinositides).

 Such molecules are termed as second messengers Many of these second messengers affect gene transcription but they also influence a variety of other biologic processes.

Structure of Cell Surface Receptors Extracellular domains Transmembrane domains Cytoplasmic or intracellular domains

Subclasses of membrane receptors:

1. G ProteinCoupled Receptors (GPCR) Are also called Serpentine receptors or 7 transmembrane segment (7tm) receptors. These receptors typically have seven hydrophobic plasma membrane-spanning domains. Receptors of this class signal through guanine nucleotide-bound protein intermediates. To date, hundreds of G proteinlinked receptor genes have been identified; this represents the largest family of cell surface receptors in humans. A wide variety of responses are mediated by the GPCRs.

Components of the hormone receptorG protein effector system

 G-protein receptors activate trimeric G-protein Activated G-protein alters the cellular concentration of a second messenger: usually cyclic AMP or Ca2+ The second messenger activates a protein kinase enzyme The protein kinase phosphorylates another enzyme and alters its activity

 Trimeric G-proteins disassemble when activated: Inactive G-protein has a bound GDP When activated: GDP dissociates, new GTP is bound This causes a to dissociate from bg a binds to adenylate cyclase, altering its activity Gs protein stimulates & activates adenylate cyclase, Gi inhibits it

 Gs and Gi are under the influence of different hormones. Hormones that induce GTP binding to Gi cause inhibition of adenylyl cyclase, resulting in lower cellular [cAMP]. Gq subunits couple to phospholipase C, generating diacylglycerol and inositol triphosphate, leading to activation of protein kinase C and the release of intracellular calcium.

Inositolphospholipid signaling pathway: Binding of a ligand to its transmembrane receptor (R) activates the G protein (Gq) This in turn stimulates a specific membranebound phospholipase C (PLC), which catalyzes hydrolysis of the phospholipid PIP2 in the inner leaflet of the plasma membrane. The resulting second messengers, IP3 and diacylglycerol (DAG), are responsible for carrying the signal to the interior of the cell

 IP3 diffuses to the endoplasmic reticulum, where it binds to and opens a Ca2+channel in the membrane, releasing stored Ca2+ Diacylglycerol remains in the plasma membrane, where italong with Ca2+ activates the enzyme protein kinase C (PKC).

Sutherland won a Nobel Prize for this work in 1971.

2. Gated ion channels The excitability of sensory cells, neurons, and myocytes depends on ion channels, signal transducers that provide a regulated path for the movement of inorganic ions such as Na+ ,K+, Ca2+ and Cl- across the plasma membrane in response to various stimuli. Ion channels are gated; they may be open or closed, depending on whether the associated receptor has been activated by the binding of its specific ligand (a neurotransmitter, for example) or by a change in the transmembrane electrical potential, Vm.

Role of voltage-gated and ligand-gated ion channels in neural transmission.

3. Receptor Enzymes A fundamentally different mechanism of signal transduction is carried out by the receptor enzymes. These proteins have a ligand-binding domain on the extracellular surface of the plasma membrane and an enzyme active site on the cytosolic side, with the two domains connected by a single transmembrane segment. Commonly, the receptor enzyme is a protein kinase that phosphorylates Tyr residues in specific target proteins; the insulin receptor is the prototype for this group.

 Other receptor enzymes synthesize the intracellular second messenger cGMP in response to extracellular signals. The receptor for atrial natriuretic factor is typical of this type.

Insulin receptor The insulin receptor has two types of subunits, and . The -subunit is on the extracellular side of the membrane, and it binds to insulin. The subunit spans the membrane. When insulin binds to the -subunit, the subunits autophosphorylate on tyrosine residues. These then phosphorylate target proteins called insulin receptor substrates (IRS). These IRSs act as the second messengers in the cell.

Nuclear Receptors and Mechanisms of Action

The family of nuclear receptors has grown to nearly 100 members, many of which are still classified as orphan receptors because their ligands, if they exist, remain to be identified. Though all nuclear receptors ultimately act to increase or decrease gene transcription, some (e.g., glucocorticoid receptor) reside primarily in the cytoplasm, whereas others (e.g., thyroid hormone receptor) are always located in the nucleus.

 After ligand binding, the cytoplasmically localized receptors translocate to the nucleus. Activated receptor binds to regulatory DNA sequences called Hormone Response Elements and initiates transcription of the target gene

General mechanism by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression.