Intracellular Receptors for Lipid-Soluble Agents

October 8, 2014 Pharmacology No comments , ,

In general, there are five basic types of receptors. They include 1. a lipid -solube ligand that crosses the membrane and acts on an intracellular receptor; 2. a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain; 3. a transmembrane receptor that binds and stimulates a protein tyrosine kinase; 4. a ligand-gated transmembrane ion channel that can be induced to open or closed by the binding of a ligand; and 5. a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein, see the post of http://www.tomhsiung.com/wordpress/2014/09/g-protein-coupled-receptors/), which in turn modulates production of an intracellular second messenger.

Today we talk about the intracellular receptors. Several biologic ligands are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors. The adequate lipid-soluble property is the prerequisite criteria as it is need for the binding between the ligands and receptors. Such ligands include, but not limited to, steroids such as corticosteroids, mineralocorticoids, sex steroids, vitamin D, thyroid hormone, and so on. These ligands activate the intracellular receptors and the consequent activated intracellular receptors stimulate the transcription of genes by binding to specific DNA sequences near the gene whose expression is to be regulated. Many of the target DNA sequences (called response elements) have been identified.


Intracellular ReceptorsThe binding of the ligand to its receptor relieves an inhibitory constraint on the transcription-stimulating activity of the receptor. Like shown in the picture on the left, where in the absence of the ligand, the receptor is bound to hsp90, a protein that appears to prevent normal folding of several structural domains of the receptor. Binding of ligand to the intracellular receptor tiggers release of hsp90 (the inhibitory constraint), which allows the DNA-binding and transcription-activating domains of the receptor to fold into their functionally active conformations, so that the activated receptor can initiate transcription of target genes.

The mechanism used by this type of ligands and receptors has two therapeutically important consequences:

1. All of these ligands produce their effects after a characteristic lag period of 30 minutes to several hours – the time required for the synthesis of new proteins (coming from the regulated genes). This means the lignad (more precisely, the gene-active ligand)cannot be expected to alter a pathologic state within minutes (the physiologic effect of the ligand). For instance, glucocorticoids will not immediately relieve the symptoms of acute bronchial asthma.

2. The effect of these agents can persist for hours or days after the agonist concentration has been reduced to zero (we set NO covalent binding here). The persistence of effect is primarily due to the relatively slow turnover of most enzymes and proteins, which can remain active in cells for hours or days after they have been synthesized. Consequently, it means that the beneficial (or toxic) effects of a gene-active ligand usually decrease slowly when administration of the ligand is stopped.

The new anti-diabetes drug GLP-1 receptor agonists

March 31, 2012 Diabetes, Drug Informatics, Pharmacology 1 comment , , ,

A GLP-1R agonist Exenatide approved by FDA.

This article comes from references available on internet. It is about a new drug called Glucagon-like Peptide-1 [GLP-1] Receptor Agonists.

So GLP-1R Agonists is analog of human glucagon-like peptide-1, and it acts as GLP-1 receptor agonist to increase insulin secretion in the presence of elevated blood glucose. Also it delays gastric emptying to decrease postprandial glucose and decreases glucagon secretion.

So what is Glucagon-like Peptide-1 [GLP-1]?

GLP-1 is one kind of native human hormones called Incretins, which is produced by the proglucagon gene in L-cells of the small intestine. GLP-1 decreases and control blood glucose by various mechanism including: [1].Liver: reduces hepatic glucose output by inhibiting glucagon release. [2]. Alpha cell: inhibits glucagon secretion. [3].CNS: promotes satiety. [4].Stomach: slows gastric emptying. [5].Beta cell: stimulates glucose-dependent insulin secretion and beta-cell differentiation and proliferation.

Thus, modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogs, and mimetics or by inhibiting its degradation has become a major focus of investigation for treating type 2 diabetes over the past decade.

Another important thing, where can we find the receptor of GLP-1?

The receptor is found on pancreatic periductal cells and β-cells and in the kidney, heart, stomach, and brain. GLP-1 receptor (GLP-1R) knockout mice have fasting hyperglycemia and abnormal glucose tolerance but are not obese.


[1].Medscape: Guideline Discusses Oral Pharmacotherapy for Type 2 Diabetes. Full reference: http://www.medscape.org/viewarticle/758426?src=cmemp
[2].Glucagon-Like Peptide 1-Based Therapies for Type 2 Diabetes: A Focus on Exenatide. Full reference: http://clinical.diabetesjournals.org/content/23/2/56.full
[3].Glucagon-Like Peptide-1 Receptor Agonists Promote Weight Loss. Full reference: http://www.medscape.org/viewarticle/757036