Hormones

Receptor Regulation
By: Ananya, Neha, Milli
Receptors
● Are not static components of the plasmolemma
● Numbers are in constant state of flux
● Numbers change with cell cycle or with a state of cellular differentiation
● Cells have varying capacity to respond to a certain hormone
○ More or less responsive depending on the specific developmental or differentiated state
of the tissue
○ May even lose their capacity to respond to a certain hormone, but gain the ability to react
to another
Hormones can regulate receptor Number
● Regulation by Hormones

Homologous Heterologous

● Receptor Regulation

Negative (down) Positive (up)

Cellular mechanisms of Decreased
Response
● Desensitization
● Downregulation
 Downregulation.

● Downregulation specifically refers to a reduction in

the total number of receptors available to be
stimulated due to prolonged receptor activation (e.g.
by chronic treatment with a pharmacological agonist
drug or prolonged inhibition of metabolism of a
neurotransmitter).
● This reduction in receptors in turn will decrease the
cell’s sensitivity to an agonist or drug.
● Downregulation occurs through endocytosis.
Internalized receptors may either be degraded in the
lysosomes or recycled back to the membrane surface
later.
● Sensitivity of target cell to hormone is decreased.
Desensitization.
● Desensitization refers to a reduced response to an agonist drug due to over activation of a
receptor (high doses, prolonged exposure to agonist).
● There is a number of mechanisms of desensitization including: loss of receptor function
through a decrease in receptor-coupled signaling components (e.g., G-proteins).
● Receptor desensitization may occur in the absence of significant changes in the number
of receptors.
● This example here demonstrates loss of receptor function; one of several types of
desensitization. As you can see on the far right, the agonist is bound to the receptor,
however, this does not result in the channel opening.
Homologous desensitization.
● Hormonally induced negative regulation of receptors is referred to as
homologous desensitization.
● This homeostatic mechanism protects from the toxic effects of hormone
excess.
● Other residues in the cytosolic domain of the B-adrenergic receptor are
phosphorylated by the receptor specific B-adrenergic receptor kinase
(BARK).
● BARK only phosphorylates the B-adrenergic receptor which facilitates B-
arrestin binding to the phosphorylated receptor.
Homologous desensitization and down
regulation of GPCRS
Heterologous desensitization.
● Heterologous desensitization occurs when exposure of the cell to one agonist
reduces the responsiveness of the cell to any other agonist that acts through a
different receptor.
● This commonly occurs through receptors that act through adenylyl cyclase
system.
● It results in a broad pattern of refractoriness with slower onset than
homologous desensitization.
● Four residues in the cytosolic domain of the B-adrenergic receptor can be
phosphorylated by pKA.
● Activity of all Gs protein- coupled receptors, not just B-adrenergic, is reduced.
 UP REGULATION

● An antagonist may increase the number of receptors.

● By preventing down regulation caused by an endogenous
agonist.
● When the antagonist is withdrawn
● The elevated number of receptors can produce an exaggerated
response.
Antipsychotics & Tardive
Dyskinesia
 SUPERSENSITIVITY

Exaggerated response
following Chronic reduction in
Receptor Stimulation
● Eg:
1. Prolonged receptor blockade
2. Chronic denervation supersensitivity
3. In cardiac ischemia
4. Hyperthyroidism
Disease resulting from
Receptor Malfunction
Loss of Function Mutations

● Loss of GPCR function is associated with hypo phenotypes of

the target tissues.
● Hypothyroidism , hypogonadism , short stature , diabetes
insipidus.
1. Simple loss of function
● Eg: Melanocortin 2 receptor

Familial glucocorticoid deficiency type 1

Autosomal Recessive
Loss of Basal activity
● Eg: Ghrelin receptor

Short stature

Autosomal Dominant
● Gain of Function Mutations
● Activation in the absence of ligand (constitutive activity)
● Increased Sensitivity to the receptors usually agonist

● Germ line activation mutation of

Arginine Vasopressin receptor 2

Increased constitutive activity

Nephrogenic syndrome of inappropriate antidiuresis

X linked dominant