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Regulation of ReceptorsAndDiseases Resulting From Receptor

Malfunction-Nimisha-HeenaM.pharm)

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Introduction

Receptors not only initiate regulation of biochemical and physiological events but

they are also subjected to homeostatic and regulatory controls

Controls: regulation of the synthesis and degradation of the receptor, association

with other regulatory proteins, and/or relocalization within the cell.

Transducer and effector proteins are regulated similarly. Modulating inputs may

come from other receptors, directly or indirectly, and receptors are almost always

subject to feedback regulation by their own signaling outputs

Two feedback mechanisms: 1.Downregulation

2.Upregulation

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1.Downregulation: hormone/agonist decreasesthe number or affinity of its receptors in a target tissue

may occur by- decreasing the synthesis of new receptors

by increasing the degradation of existing receptors

or by inactivating receptors

purpose is to reduce the sensitivity of the target tissue when hormone levels are high

the response to hormone declines, although hormone levels remain high

Mechanism: The Insulin ReceptorInsulin

levels(blood)

Binding to the receptor Hormone-receptor complex

Degradation of

Insulin

endocytosi

s

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1.Upregulation: hormone/agonist increasesthe number or affinity of its receptors in a target tissue

may occur by- increasing the synthesis of new receptors

by increasing the synthesis of existing receptors

or by activating receptors

Ex: increased number of cytochrome P450;with dioxin

growth hormone increases the number of its receptors in skeletal muscle and liver

A hormone also can up-regulate the receptors for other hormones.

estrogen not only up-regulates its own receptor in the uterus, but it also up-regulates the

receptors for LH in the ovaries

Upregulation and downregulation can also happen as a response to toxins or hormones, forexample in pregnancy, hormones cause cells in the uterus to become more sensitive to

oxytocin

Receptor agonists:downregulate

Receptor antagonists:upregulate

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ROLE OF RECEPTORS IN VARIOUSBIOLOGICAL PROCESSES INCLUDINGDISEASES RESULTING FROM RECEPTOR

MALFUNCTION

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Nicotinic Acetylcholine Receptors

nAChRs, are cholinergic receptors that form ligand-gated ionchannelsin the plasma membranes of certain neurons and

on the postsynaptic side of the neuromuscular junction.

As ionotropic receptors, nAChRs are directly linked to ion

channels and do not use second messengers.

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Role of Nicotinic Receptors Skeletal Muscle:At the neuromuscular junction, ACh

interacts with nicotinic ACh receptors and induces an

immediate, marked increase in cation permeability.

Upon activation by ACh, the nicotinic receptors intrinsic

channel opens for about 1 ms, admitting ~50,000 Na+ ions.

The channel opening process is the basis for the localized

depolarizing EPP (excitatory postsynaptic potential) within

the end plate, which triggers the muscle AP (action potential)

and leads to contraction.

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Myasthenia Gravis

Myasthenia gravis is a neuromuscular disease characterizedby weakness and marked fatigability of skeletal muscle.

The defect in myasthenia gravis is in synaptic transmission

at the neuromuscular junction, such that mechanical

responses to nerve stimulation are not well sustained.

Myasthenia gravis is caused by an autoimmune response

primarily to the ACh receptor at the postjunctional endplate.

These antibodies reduce the number of receptors available.

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Serotonin Receptors

The serotonin receptors, also known as 5-HT receptors, are a group ofG protein-coupled receptors (GPCRs) and ligand-gated ion channels(LGICs) found in the central and peripheral nervous systems.

They mediate both excitatory and inhibitory neurotransmission.

The serotonin receptors are activated by the neurotransmitter serotonin,

which acts as their natural ligand.

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ROLE OF SEROTONIN RECEPTORS

The serotonin receptors modulate the release of manyneurotransmitters, including glutamate, GABA, dopamine,

epinephrine / norepinephrine, and acetylcholine, as well as

many hormones, including oxytocin, prolactin, vasopressin,

cortisol, corticotropin, and substance P, among others.

The serotonin receptors influence various biological and

neurological processes such as aggression, anxiety,

appetite, cognition, learning, memory, mood, nausea, sleep,

and thermoregulation.

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VEGF AND VEGFR

Vascular endothelial growth factor (VEGF) is a signal proteinproduced by cells that stimulates vasculogenesis and

angiogenesis.

It is part of the system that restores the oxygen supply to

tissues when blood circulation is inadequate.

VEGF's normal function is to create new blood vessels

during embryonic development, new blood vessels after

injury, muscle following exercise, and new vessels (collateral

circulation) to bypass blocked vessels.

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EGF AND EGFR

EGF (Endothelial Growth Factor) results in cellular proliferation,

differentiation, and survival.

The epidermal growth factor receptor is the cell-surface receptorfor members of the epidermal growth factor family (EGF-family)

of extracellular protein ligands.

The epidermal growth factor receptor is a member of receptor

tyrosine kinases.

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CANCER

Mutations that lead to EGFR overexpression(known as upregulation) oroveractivity have been associated with a number of cancers, includinglung cancer, and glioblastoma multiforme.

Mutations involving EGFR could lead to its constant activation, whichcould result in uncontrolled cell division a predisposition for cancer.

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THANK YOU

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