Receptors, intracellular

Movement to intracellular receptors (steroid hormones a form of diffusion)... 

Some hormones have intracellular receptors others bind to receptors on the plasma membrane. 

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

Amine hormones include the thyroid hormones and the catecholamines. The thyroid hormones tend to be biologically similar to the steroid hormones. They are mainly insoluble in the blood and are transported predominantly (>99%) bound to proteins. As such, these hormones have longer half-lives (triiodothyronine, t3, = 24 h thyroxine, T4, = 7 days). Furthermore, thyroid hormones cross cell membranes to bind with intracellular receptors and may be administered orally (e.g., synthryoid). In contrast to steroid hormones, however, thyroid hormones have the unique property of being stored extra-cellularly in the thyroid gland as part of the thyroglobulin molecule. 

The signal is what starts everything off. Signals take a variety of forms, but for our purposes there are only two. The first type are signals that go into the cell, bind to internal receptors, and exert their effects. Steroid hormones, vitamin D, thyroid hormone, and retinoids are the only members of this class. All of the intracellular receptors ultimately activate the transcription of regulated genes. The common feature of signals that enter the cell is that they are all small lipophilic molecules that can cross the cell membrane. 

D-myo-inositol 1,4,5-trisphosphate (l(1,4,5)P3) is a second messenger that liberates Ca2+ from the endoplasmic reticulum via intracellular receptors. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

FIGURE 52-2 There are two modes of hormonal action. (A) Activation of cell-surface receptors and coupled second-messenger systems, with a variety of intracellular consequences. (B) Entry of hormone into the target cell, binding to and activation of an intracellular receptor and binding of the receptor-hormone complex to specific DNA sequences to activate or repress gene expression. DAG, diacylglycerol HRE, hormone-response element. 

The vast majority of the actions for which the estrogens in tissues are known are mediated by one of their intracellular receptors and imply the modification of the expression of extensive groups of genes that vary from one... 

There is growing evidence on the existence of ERs anchored to specific regions of the plasmatic membrane of target cells. These receptors mediate fast actions of estrogens that are executed by their own signaling mechanisms and that are different from the actions used at the genome level by the intracellular receptors. 

Receptors are proteins or glycoproteins found either on the surface of the target cell or located within the cell interior. The surface receptors engage peptide hormones which, being hydrophilic, do not traverse the fatty plasma membrane intracellular receptors combine specifically with particular steroids or tri-iodothyronine, T3. 

Intracellular Receptors These receptors are in the cytoplasm or nucleus. Drugs or endogenous ligand molecules have to pass through the cell membrane (a lipid bUayer) to interact with these receptors. The molecules must be hydrophobic or coupled to a hydrophobic carrier to cross the cell membrane. 

We discuss later a number of receptor classes and analyze how signals are transduced. These receptors are G-protein coupled receptors (GPCRs), ion channel receptors, tyrosine kinases, and intracellular receptors. A list of selected... 

The main drug targets are enzymes, intracellular receptors, and extracellular (cell surface) receptors. Drugs are normally designed to interact with these entities either as agonists or antagonists to achieve control over the disease pathway. 

The important receptors are GPCRs, ion channels, tyrosine kinases, and intracellular receptors. Refer also to Appendix 3 for specific functions of the drugs in interacting with receptors. 

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