Regulation of Receptors And Diseases Resulting From Receptor Malfunction

-Nimisha

-Heena (M.pharm)

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

1.Downregulation:
hormone/agonist decreases the 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 Receptor

Insulin levels(blood) Binding to the receptor

Hormone-receptor complex
endocytosi s

Degradation of

Insulin

1.Upregulation:
hormone/agonist increases the 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, for example in pregnancy, hormones cause cells in the uterus to become more sensitive to oxytocin Receptor agonists:downregulate Receptor antagonists:upregulate

ROLE OF RECEPTORS IN VARIOUS BIOLOGICAL PROCESSES INCLUDING DISEASES RESULTING FROM RECEPTOR MALFUNCTION

Nicotinic Acetylcholine Receptors

nAChRs, are cholinergic receptors that form ligand-gated ion

channels in 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.

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.

Myasthenia Gravis
Myasthenia gravis is a neuromuscular disease characterized

by 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.

Serotonin Receptors
The serotonin receptors, also known as 5-HT receptors, are a group of

G 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.

ROLE OF SEROTONIN RECEPTORS

The serotonin receptors modulate the release of many

neurotransmitters, 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.

VEGF AND VEGFR

Vascular endothelial growth factor (VEGF) is a signal protein

produced 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.

EGF AND EGFR

EGF (Endothelial Growth Factor) results in cellular proliferation,

differentiation, and survival. The epidermal growth factor receptor is the cell-surface receptor for 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.

CANCER
Mutations that lead to EGFR overexpression (known as upregulation) or

overactivity have been associated with a number of cancers, including lung cancer, and glioblastoma multiforme. Mutations involving EGFR could lead to its constant activation, which could result in uncontrolled cell division a predisposition for cancer.

THANK YOU