RECEPTOR

PHARMACOLOGY
 SYNOPSIS
• ION CHANNEL RECEPTORS
• TRANSMEMBRANE ENZYME LINKED RECEPTORS
• TRANSMEMBRANE JAK STAT BINDING RECEPTORS
• RECEPTORS REGULATING GENE EXPRESSION
• REGULATION OF RECEPTORS
• FUNCTIONS OF RECEPTORS
• RECENT ADVANCES
• SUMMARY
RECEPTORS
• Molecules that are responsible for majority of biochemical & metabolic process in
the body.
ION CHANNEL RECEPTORS
• Ligand gated ion channel
• Responsible for regulation of flow of ions across the membrane
• Activity is regulated by binding of ligand to the channel
• Response to receptor is rapid,
• Duration: milliseconds
• Causes depolarization or hyperpolarization or changes in the cytosolic ionic composition depending on the ion that flows through it.
• Eg: Nicotinic cholinergic, GABA A ,Excitatory AA- Glutamate and 5HT3 receptors fall in this category.
TRANSMEMBRANE ENZYME LINKED RECEPTORS

• Consists of those receptors having cytosolic enzyme activity as an integral component of their structure &function.
• Function: Binding of ligand to an extracellular domain activates or inhibits the cytosolic enzyme activity
• On binding of ligand to receptor subunit, the receptor undergoes conformational changes, converting from its inactive form to active
kinase.
• Activated receptor auto phosphorylates & then phosphorylates tyrosine residues on specific proteins
• Duration: mins to hours
• Egs: epidermal growth factors, platelet derived growth factor, atrial natriuretic peptide, insulin
JAK –STAT BINDING RECEPTOR
PATHWAY
• COMPONENTS:
• RECEPTOR
• JANUS KINASE(JAK)
• SIGNAL TRANSDUCER & ACTIVATOR OF TRANSCRIPTION(STAT)
Mechanism of action
CONTD… .
• THESE RECEPTORS HAVE NO INTRINSIC ENZYMATIC ACTIVITY
• Binding of cytokine causes dimerization of receptors
• Recruits a separate intracellular tyrosine kinase named as JANUS KINASE
• JAK binds to the cytosolic tails of the receptors.
• JAK transphosohorylates & leads to the phosphorylation of STATs( SIGNAL TRANSDUCER & ACTIVATOR OF TRANSCRIPTION)
• STATS translocate to the nucleus & regulates transcription.
MECHANISM
RECEPTORS REGULATING GENE
EXPRESSION
• Also called as Nuclear receptors
• Intracellular receptors
• Ligand must diffuse into the cell to interact with the receptor
• Ligand must have sufficient lipid solubility to be able to move across the target cell membrane.
• Activated ligand receptor complex migrates or trans locates to the nucleus ,where it binds to specific DNA sequences
• Cellular responses are only after 30 minutes or more
• Duration of the response : Hours - Days
• Regulation of gene expression
Contd………..
• Molecular Structure:

 The N-terminal domain displays the most heterogeneity.

 It harbours the AF1 (activation function 1) site.

 The core domain of the receptor is highly conserved and consists of the structure responsible for DNA recognition and binding.

 It is the highly flexible hinge region in the molecule that allows it to dimerise with other NRs.

 The C-terminal domain contains the ligand-binding module and is specific to each class of receptor.
Contd….

Clinical Significance:

1.NRs are very important drug targets, being responsible for the biological effects of approximately 10–15% of all prescription drugs.

2.NRs also regulate expression of many drug metabolizing enzymes and transporters.

3.Many illnesses are associated with malfunctioning of the NR system, including inflammation, cancer, diabetes, cardiovascular disease,
obesity and reproductive disorders.
Regulation of Receptors
 Receptors exist in a dynamic state, i.e. their density and efficacy to elicit a response is subject to regulation by the level of on-going
activity, feedback from their own signal output and other pathophysiological influences.

 The mechanisms involved may be unmasking of receptors or their proliferation (up regulation) or accentuation of signal amplification
by the transducer.

 Eg. – Estrogens increase the density of oxytocin receptors on the myometrium, and the sensitivity of uterus to contractile action of
oxytocin increases progressively during the third trimester of pregnancy, especially near term.
Contd….
 Conversely, continued / intense receptor stimulation causes desensitization or refractoriness: the receptor becomes less efficient in
transducing response to the agonist.

 The mechanisms by which this is brought about is:

 Masking or internalization of the receptor or impaired coupling of the transducer to the receptor. Eg. In case of β adrenergic
receptors.

 Decreased synthesis/ increased destruction of receptors (down regulation). Eg. In tyrosine kinase receptors.

Eg. Includes patients of bronchial asthma being treated continuously with β adrenergic agonists gradually become less responsive .
Functions
These are:

1. To propagate regulatory signals from outside to inside the effector cell when the molecular species carrying the signal cannot
itself penetrate the cell membrane.

2. To amplify the signal.

3. To integrate various extracellular and intracellular regulatory signals.

4. To adapt to short term and long term changes in the regulatory events and maintain homeostasis .
Recent Advances

 GPR83:
 Is currently classified as an orphan receptor.
 Mainly localised in the mouse to the CNS.
 It has been implicated in behavior, learning, and metabolic regulation.
 A biologically active peptide, PEN is now identified as a ligand activating GPR83 .
Contd….

 CSF1R:
 Inhibition of CSF1R by a tyrosine kinase inhibitor results in the blockade of microglial proliferation on transgenic mouse model of
Alzheimer's-like pathology.
 There was improved memory and behavioral performance as well as prevention of synaptic degeneration.
 This suggests the therapeutic strategy of modifying CSF1R activation could ameliorate Alzheimer's disease .
Contd….
 Sigma receptor:
 It has been a ‘receptor-in-waiting’.
 Revealed as ‘fourth’ opioid receptor.
 Responds to nociceptin / orphanin.
 Has functional impact, in particular in the nervous and cardiovascular systems.

 Sigma-2 Receptors:
 Receptor activation produces both transient and sustained increase in Ca 2+ and cytotoxic effects.
 Sigma-2 agonists induced apoptosis in drug-resistant cancer cells.
 Also, enhanced the potency of DNA damaging agents.
 Sigma-2 receptor agonists may be useful in treatment of drug-resistant cancers.
SUMMARY