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What is common to all ligands of the nuclear receptor subfamily

Aromatic groups that are hydrophobic


What are the distinguishing features of cNOS

Although cNOS is constitutively expressed, its enzymatic activity is induced by Ca2+/Calmodulin. This activity is short-lived and leads to the generation of pmol amounts of NO


What is the major difference between nuclear receptor transcription factors that bind to DNA as homodimers and heterodimers in terms of the sequence with which they interact

Homodimers bind to palindromic sequences whereas heterodimers bind tandem repeat sequences


Heterodimeric intracellular receptors are always bound to DNA, even in the absence of ligand binding, T or F



Explain what happens to nuclear receptors following ligand binding

Inhibitory proteins hold the receptors in an inactive state. Binding to the ligand removes the inhibitors leading to a conformational change. The receptors can now interact with coactivators to direct transcription


How does sildenafil citrate act to treat erectile dysfunction

ViagraTM acts downstream of NO(g) to inhibit phosphodiesterase 5. Phosphodiesterase-5 converts cGMP back to GMP and counteracts guanylyl cyclase. Increases in cGMP by the inhibition of PD-5 leads to the relaxation of vascular smooth muscles increasing blood flow to the penis.


Explain the mechanism by which heterodimeric receptor transcription factors act

Heterodimeric receptors are located exclusively in the nucleus. They act as transcriptional repressors in the absence of ligand by recruitment of histone deacetylases and as activators in the presence of ligand by recruitment of histone acetylases


Overproduction of NO in the lungs and intestines can cause what diseases

Rheumatoid arthritis, Crohn’s disease and asthma


Give an example of a small molecule that binds to an intracellular receptor



What is the name of the enzyme that catalyses NO formation

Nitric oxide synthase (NOS)


In the CNS, nNOS is tethered close to NMDA-type glutamate receptors. Explain the role of NO in the brain

nNOS in the brain can respond to the Ca2+ increases near the open NMDA channel. This has implications in synaptic plasticity. Glutamate is produced by a presynaptic terminal and this activates glutamate receptors, especially NMDA receptors, which in turn stimulate the NO pathway in the postsynaptic terminal. NO produced in this way travels to the presynaptic terminal and increases the production of glutamate, thus creating the state of long-term potentiation.


Explain the mechanism by which homodimeric receptor transcription factors act

Upon ligand/hormone binding, homodimeric transcription factors translocate to the nucleus following the release of inhibitor proteins that are bound to its inactivated form and anchor it to the membrane. Once allowed to translocate to the nucleus these homodimers can influence gene transcription.


iNOS plays a crucial role in the immune response, T or F



What neurotransmitter can cause the activation of NOS enzymes

Autonomic nervous system release of acetylcholine activates NOS enzymes in endothelial cells


What is the name of the cofactor that interacts with heterodimeric intracellular receptors

RXR cofactor


Nuclear receptors are essentially transcription factors activated by hydrophobic ligands, T or F



Give an example of an inhibitor protein that anchors homodimeric receptors to the membrane of the cell



Give an example of a lipid-soluble that binds to an intracellular receptor

Retinoic acid


Explain the role of nitrous oxide in the immune system

NO acts in the immune system by killing bacteria and parasites and inducing programmed cell death. iNOS in inflammatory cells uses NO as a cytostatic and cytotoxic agent. This involves much higher amounts of NO and is due to its effects as a free radical causing cell death


What kinds of stimuli induce iNOS expression

LPS, IFN-? and IL-1


How is NO naturally produces

Produced by two successive oxidations of L-arginine to L-citrulline


What are the two main categories of NOS enzymes

Constitutive NOS and Inducible NOS


Give examples of homodimeric nuclear receptors

Glucocorticoid and oestrogen receptor


There are two subgroups of constitutive NOS enzymes, eNOS and nNOS, what are the main differences between these enzymes

Endothelial or eNOS is a membrane tethered isoform of the cNOS enzyme. It is present in endothelium, cardiac myocytes renal mesangial cells amongst others. nNOS or neuronal NOS is a cytosolic NO receptor enzyme. It is present in the central nervous system, NANC neurons and enteric nervous system.


Explain how NO leads to the relaxation of vascular smooth muscle

Acetylcholine released activates NOS enzymes which convert arginine to NO.NO diffuses across membranes and binds to guanylyl cyclase and activates it. Activation guanylyl cyclase converts GTP to cGMP. Increases in cGMP activate the cGMP-dependant protein kinase-G which acts to increase myosin light chain phosphatase (MLCP) levels ultimately leasing to the relaxation of smooth muscle.


Nitrous oxide is a gas that binds to an intracellular receptor, it is known as a free radical. What is meant by this term

NO is a free radical meaning that it is a highly reactive species that contains an unpaired electron in its outer shell. It is very unstable with a half-life of roughly 5-10secs


Explain the role of nitroglycerine in the treatment of angina

Nitroglycerine breaks down in vivo to generate NO. NO then acts to relax the coronary blood vessels thus decreasing the load on the heart and increasing heart blood supply


The effects of the ligands are modified in different tissues by the expression of different coactivators, T or F



Give examples of heterodimeric nuclear receptors

Vitamin D, thyroid hormone and retinoic acid receptors


Describe the difference between the early primary and delayed secondary response to intracellular receptor activation

The early primary response occurs within 1-6 hours. These effects are relatively slow because they are transcription factors that regulate gene transcription. The delayed secondary response however takes 6-48hours. This is the case because the genes upregulated in primary response include these transcription factors that then mediate the secondary response