PHYSIOLOGY

Dr.Ahmad Al-Qawasmi

2025
Study smarter, not harder!
 ❖ Signal transduction
• Components of signal transduction:
➢ Ligand which is the signaling molecule (such as hormones)
➢ Receptors which are specific proteins that bind to specific ligands
➢ Intracellular signaling proteins (mediatory proteins) and Target protein

• The importance of signaling is to allow cells to respond to

environmental changes such as temperature changes and O2 availability
➢ Signals can be inhibitory stopping or slowing many mechanisms
➢ Not all of the receptor must be bound to induce a response

• Signals can act locally or at a distance

➢ Locally (local mediators) acts on a short distance
 Autocrine: The target cell is same as the one that secrete the ligand
 Paracrine: The target cell is near to the cell that secretes the ligand
➢ At a distance (Circulating) where the hormone is secreted into the
blood to be transported into the target cells (Endocrine)

• Responses can be fast or slow depending on the mechanism induced to make changes the responding cell
o Fast response (seconds – minutes) o Slow response (hours – days)
✓ In the cytoplasm ✓ In the nucleus
✓ Simple cellular modifications such as the altering ✓ Altering gene expression
the activity of enzymes or cytoskeletal proteins

• Signals are amplified (1 ligand can produce a very large response inside the cell)

• Types of signaling:
➢ Contact-dependent via proteins in the plasma membrane
➢ Secreted signals including Autocrine, Paracrine,
Endocrine and Synaptic (via NTs)

• Chemical classification of hormones:

Lipid soluble hormones Water soluble hormones

Non-polar Polar
 Require transport proteins in plasma  Free in the plasma (without plasma proteins)
 Cross the plasma membrane easily m  Can’t cross plasma membrane m

 Amines: tyrosine and tryptophan derivatives m

 Steroids: cholesterol derivatives (Testosterone,  Prostaglandins (Eicosanoids): Arachidonic acid m
Estradiol, Cortisol, Progesterone) derivatives (20 Carbons, 4 double bonds) m
 Thyroid: such as T3 and T4 (thyroxine)  Polypeptides: less than 100 A.A (such as ADH) m

✓ The only lipophilic amines  Proteins: more than 100 A.A (such as growth hormone) m
 Nitric oxide (NO): has a gaseous nature  Glycoproteins: such as FSH, LH, TSH and hCG m

✓ They can be either alpha (common) or beta (specific)

• Ligands can bind to:

➢ Receptors on the cell surface: including large and polar ligands such as NTs & water soluble ligands
➢ Receptors on the cell surface: including small and non-polar ligands
 They can bind on both receptors
• Preprohormones: Large precursor molecule that prohormones are derived from
• Prohormone: Smaller precursor with a long-chained polypeptide that is cut and spliced together
➢ Preproinsulin → Proinsulin → Insulin (active)
• Prehormone: Molecules secreted by endocrine glands that are inactive until changed into Hormones
➢ T4 converted to T3 (tri-iodothyronin)

• Synthesis and secretion of peptide hormones:

➢ In the nucleus, DNA is transcribed into RNA which migrate to the cytosol
(ribosomes) to be translated
➢ Then they are packed in the ER and modified in Golgi
➢ Stored until a stimulus reaches to stimulate secretion

Mode of
Hormone Type The Hormone
secretion
Epinephrine (Adrenaline), Norepinephrine, Dopamine
Endocrine
Amino Acids derivatives T4, T3 (thyroxine)
(Amines) [All the above are Tyrosine derivatives]

Histamine Paracrine

Estrogens, Progesterone, Androgens, Testosterone (sex hormones)

Steroid hormones and corticosteroids, Cortisol, Estradiol, Aldosterone, Androgens Endocrine
Calcitriol (1,25-Dihydroxycholecalciferol)

TRH, GnRH, CRH, GHRH, Somatostatin, ACTH, TSH, FSH, LH,

PRL, GH, Posterior pituitary, Oxytocin, ADH, Calcitonin, Insulin,
Peptide and protein
Glucagon, Somatostatin, Somatomedin C (IGF-I), PTH, HCG, Endocrine
hormones
HCS, or HPL, Renin, ANP, Gastrin, CCK, Secretin, GIP,
Somatostatin, Leptin, growth hormones

Eicosanoid (Arachidonic
Prostaglandins Paracrine
acid derivatives)
Glycoproteins FSH, LH, TSH and hCG (human chorionic gonadotropin) Endocrine

• Different density for hormones gives different response

➢ Priming effect (Up regulation)
✓ Increase the number and affinity of receptors on the target cells
✓ Greater response by the target cell
➢ Desensitization (Down regulation)
✓ Decrease in number and affinity of receptors on target cell
✓ Caused by the prolonged exposure to high concentration of hormone (especially polypeptide)
✓ Example: Insulin in adipose tissue (Diabetes 2)
✓ Pulsatile (not continuous) secretion may prevent downregulation

• Normal tissue responses are produced only when hormones are present within physiological range
• Half-life is time required for the blood hormone concentration to be reduced to half the reference level
➢ It is affected by affinity and Kd
 Lower Kd = Higher affinity = lower half life
 Kd is inversely related to the affinity
• Dissociation constant (Kd): The concentration of a ligand that is required to occupy 50% of the receptors
• The type of response to a hormone depends on the type of hormone, its receptor and the target cell
• Responsiveness (strength of the response) of target cell to a receptor depends on Concentration of
hormone & Abundance cell receptor
• Receptor-hormone binding have characteristic properties, such as:
➢ Specificity: It is a description of how favorable the binding of the ligand for the receptor is
➢ Saturation: The ratio and number of bound hormones to receptor
➢ Affinity: It is how strong the binding is between receptor and certain ligand depends on the
chemical structure, strength and number of bonds formed by the hormone
 It can be judged by Kassociation or Kdissociation and ∆Go

• Three major classes of surface receptors for signaling:

1. Ion-channel linked receptors
• A ligand binds to the receptor, opening or closing a channel

2. G-protein coupled receptors (GPCR)

• They are transmembrane proteins that have 7 transmembrane helical domains
➢ GPCR ligands include Neurotransmitters (NT), Hormones (H) or even light
➢ Targets of GPCRs are enzymes or ion channels
The first discovered G-protein
• GPCR are linked to G proteins is heterotrimeric = made from 3
coupled receptor was Rhodopsin
different subunits (α, β, γ)
➢ It exists in retina, used for
➢ α and γ are lipid anchored (covalent bonds) to the cytosolic
low light vision which is
surface of the membrane
activated by light
• Mechanism of Activation of GPCRs:
➢ Binding of ligand to extracellular domain of GPRs induces conformational change that allows
cytosolic domain of the receptor to bind to inactive G protein activating G-proteins
➢  subunit activation (bind GTP instead of GDP), causing dissociation into ( + )
➢ Each subunit activates its target
➢ After the end of the response, all subunits reassociate together
 α subunit become ADP bound (inactive), and re-associate to the  complex
•  subunits can change the activity of their target
➢  inhibits one of several isoforms of Adenylate Cyclase, contributing to rapid signal turn off
➢  complex is inhibitory for  subunit, because when they are associated together is  inactive

• G-proteins have many types according the activity of their  subunit:

➢ Gs : Activate Adenylyl cyclase, increasing cAMP which activates Protein kinase A (PKA)
 Linked to -adrenergic (epinephrine) receptor & receptors of Glucagon, serotonin & vasopressin
➢ Gi : Inhibits Adenylyl cyclase, Decrease cAMP
 2 -adrenergic receptor
 Ach Muscarinic receptor (Its G subunits activate K+ channels, changing membrane potential)
➢ Gq: Activates Phospholipase C (PLC), produce IP3 & DAG kinase: Adds phosphate from
 1-adrenergic receptors causing vasoconstriction ATP (phosphorylation)
 GnRH receptor phosphatase: Removes
➢ Go: Activate PLC, produce IP3 & DAG phosphate (dephosphorylation)
 Acetylcholine [Ach] receptors in endothelial cells
• hypothalamus secretes GnRH (gonadotropin releasing hormone) binding its receptor on the anterior
pituitary gland (Gq) inducing the secretion of FSH &LH to go to the future ovaries by exocytosis
• The signal should be turned off to avoid over regulation, could happen by different ways:
➢ GTPase hydrolyzes GTP to GDP + Pi, so G rebinds to the inhibitory  complex
➢ Phosphodiesterase catalyzes hydrolysis of cAMP to AMP (cAMP + H2O ➔ AMP)
 Activated by either -Arrestin or PKA (negative feedback)
➢ Receptor desensitization by -Arrestin which can bind (block) G-protein, activate phosphodiesterase
or even promote clathrin-mediated endocytosis of the GPCR
➢ Protein Phosphatase catalyzes removal (by hydrolysis) of phosphates, inhibiting target protein

• GTP-binding proteins (G-proteins) include: Initiation & elongation factors, Ras, Rab, ARF, Ran, Rho

GAPs GEF
• GTPase Activating Proteins • Guanine Nucleotide Exchange Factors
• Promote GTP hydrolysis • Promote GDP/GTP exchange
• G has innate capability for GTP hydrolysis • An GPCR normally serves as GEF for a
due to its arginine residue required for the heterotrimeric G-protein ()
activity of a GAP

3. Enzyme linked receptors

• It is classified into:
A. TKRs (Tyrosine Kinase Receptors)
• They contain intrinsic Tyrosine kinase on its intracellular part of the receptor
➢ Includes receptors for growth factors (NGF, EGF. PDGF), insulin and Src
➢ N terminal extracellular ligand-binding domain, single TM domain, cytosolic C-terminal domain
with tyrosine kinase activity

• Mechanism of activation of TKRs:

➢ When Ligand bind to receptor, it induces dimerization (cross linking) of 2 units
➢ Autophosphorylation of tyrosine residues in the receptor (cross phosphorylation)
➢ Phosphorylation increases kinase activity or phosphate groups can bind to other molecules
 Insulin pathway involves the activation of IRS (Insulin receptor substrates or insulin downstream
targets) by phosphorylation which stimulates glycogen, fat and protein synthesis (anabolic
reactions), stimulates insertion of GLUT-4 proteins to facilitate entrance of glucose into the cell
(Glucose uptake) and stimulates growth & gene expression

B. NRTKs (Non-receptor tyrosine kinase)

• TK is non-covalently associated to these receptors, it’s not part of the receptors
➢ Such as cytokine receptors, T & B cell receptors
➢ Structure: N-terminus (extracellular ligand-binding domain), transmembrane -helix and C-
terminus (cytosolic domain) without any catalytic (kinase) activity
• Activation is similar to that of RTKs:
➢ ligand binding causes cross phosphorylation of associated tyrosine kinases that phosphorylate the
receptor, providing phosphotyrosine binding sites for recruitment of proteins with SH2 domains
• Two kinds of kinases associate with NRTKs:
➢ Src family protein kinases - B and T cell
➢ Janus kinases (JAK) required for signaling from cytokine receptors (Leptin receptor)
• Leptin bind its receptor, induces phosphorylation of JAK 2 that induces phosphorylation of Stat3
molecules which dimerize and enter the nucleus to induce transcriptions of certain targets
➢ Leptin receptor exists as a homodimer (two identical parts)
➢ Leptin is an important hormone of satiaty, and lipid-tissue metabolism

C. Receptors can be linked to or associated with other enzymes

• Protein-tyrosine phosphatases: Remove phosphates thereby terminate tyrosine kinases signals
• Serine/ threonine kinases such as TGF-β
• Guanylyl cyclase (GC) receptors: Receptor guanylyl cyclase has guanylyl cyclase as a part of it
➢ it is involved in ANP (Membrane receptor) & NO, CO signaling (Soluble receptor)

• ANP (Atrial Natriuretic Peptide) is an antihypertensive agent (lowering blood pressure)

• NO which is an antiplatelet and vasodilator
➢ NO is synthesized by NOS (nitric oxide synthase) from the precursor arginine which is responsive
to GPCR in the blood vessels linked to Gαo
➢ NO receptor is an enzyme-linked receptor linked to guanylate cyclase which induces the formation
of cGMP causing the activation of PKG and so muscle relaxation (vasodilation)

❖ Steroid receptors
• Steroid receptors are located in cytoplasm and in the nucleus (nuclear hormone receptors)
• It activates genetic transcription
➢ The receptor has 2 main regions, ligand (hormone)-binding protein & DNA-binding protein
➢ Binding of a steroid hormone causes dimerization (forming homodimer) which is translocated into
the nucleus, and binds to a specific region on the DNA called HRE
✓ HRE (hormone responsive element) it is a region of DNA where the DNA-binding protein binds

❖ Thyroid receptors
• The mechanism of thyroid hormones:
➢ T4 passes into cytoplasm and is converted to T3 by iodinase
➢ The receptor located in nucleus (TR receptor dimerizes with RXR receptor forming heterodimer)
 Retinoid X Receptor binds 9-cis-retinoic acid (vitamin A derivative)
 DNA-binding domain can then bind to HRE, Stimulating gene transcription
• This Mechanism acts in: Growth & Metabolism, CNS, Cardiovascular and many other systems

• Hormonal activity depends on the concentration of free hormone in the plasma, carrier-bound, receptor-
bound hormones, and clearance
➢ Clearance is the rate of disappearance from plasma / concentration In plasma
• Thyroid hormones (Thyroxine and Triiodothyronine) are highly bound to proteins in the plasma
protecting it from clearance (low clearance rate), causing its half-life to be long
• Protein hormones (Thyrotropin, Insulin & Antidiuretic hormone) is less bound to protein in the plasma
(high clearance rate), causing its half-life to be short
• Specific transport proteins in the plasma, include:
➢ Corticosteroid binding globulin (CBG, transcortin) binds cortisol and aldosterone
➢ Thyroxine binding globulin (TBG) binds T4 and T3
➢ Sex hormone binding globulin (SHBG) binds testosterone and estrogen
• Non-specific transport proteins, include:
➢ Albumin binds most steroids, T4 and T3
➢ Transthyretin (prealbumin) binds T4 and some steroids

❖ Messengers
• First messengers: extracellular ligand
• Second messenger: intracellular messenger Super important
• Third messengers: nuclear messenger0

• Examples of 2nd messengers: cAMP, cGMP, IP3 & DAG, Ca+2, PIP3
֎ cAMP: most common
• Synthesis: Adenylate cyclase (large transmembrane protein) converts ATP into cAMP
• Degradation: cAMP phosphodiesterase
• Action of cAMP:
➢ Its target is cAMP-dependent protein kinase also called protein kinase A (PKA)
➢ PKA is a tetramer of catalytic and regulatory subunits (activated by dissociation of these subunits)
➢ PKA has 2 Functions: phosphorylation of target proteins & changing gene expression by:
 PKA can act as a third messenger where it phosphorylates CREB (CRE binding protein) in the
nucleus to bind (CRE) region activating transcription of specific gene
 CRE (Cyclic-AMP Response Element) is a regulatory DNA sequence
• Hormones use cAMP: FSH, LH, ACTH, TSH, CRH, hCG, PTH, Calcitonin, Glucagon, GHRH,
Epinephrine, norepinephrine and Prostaglandin I
• Pathogens can alter cAMP production (abnormalities in cAMP production)
➢ Cholera toxin activates α subunit of Gs, causing it to be continuously active stimulating adenylyl
cyclase indefinitely → This causes ion channels in GI tract that export chloride to produce a net
efflux of chloride ions Cl- and water, leading to severe diarrhea

֎ cGMP (cyclic guanine monophosphate)

• Produced from GTP by guanylyl cyclase
• Target: activates cGMP-dependent kinases (PKG) or other targets
• Examples on signaling pathway that produces cGMP as a 2nd messenger:
➢ G-protein Coupled rhodopsin photoreceptor in rod cells of retina
➢ Nitric oxide signaling & ANP signaling

֎ IP3 and DAG

• Phospholipase-C (PLC) that splits PIP2 (Phosphatidylinositol 4,5-bisphosphate) into DAG & IP3
➢ DAG: diacylglycerol / IP3: inositol 1,4,5- triphosphate
➢ PIP2 is a minor phospholipid in inner leaflet of the plasma membrane bilayer
• PIP2 hydrolysis is activated by both GPCRs and TKRs via different forms of PLC
➢ Phospholipase-C beta (PLC-β) is stimulated by Gq proteins
➢ Phospholipase-C gamma (PLC-γ) has SH2 domains that allow binding to activated TRKs
• DAG still connected to PM, but IP3 become free in the cytosol, and both act as 2nd messenger
• IP3 binds to a receptor on the endoplasmic reticulum (ER) membrane which results in opening calcium
ion channels on ER membrane and release of calcium ions from their stores into the cytosol increasing
intracellular calcium levels → activating a protein kinase C (PKC)
➢ SERCA channels: Turns off the calcium signal by pumping calcium ions back to their stores in
the ER to bring calcium levels back to their normal levels
• DAG stimulates protein kinase C (PKC) signaling pathway, which activates other targets
➢ including t0he MAP kinase cascade
• Hormones use IP3, DAG: GnRH, Gastrin, Oxytocin, TRH, ADH (V1), Histamine (H1), Angiotensin II

֎ Ca+2
• The effect of intracellular Ca+2 is mediated by the Ca+2 binding protein calmodulin, forming
Ca+2 – calmodulin complex which binds to other target proteins, regulate their activity such as Ca+2
calmodulin dependent kinases (CaM-kinases), Adenylyl cyclases, Phosphodiesterases & phosphatases

֎ PIP3
• PIP2 is phosphorylated by PI 3-kinase producing PIP3
• It can be activated in the GPCR or TKR pathways
• It contributes in the survival of the cell by inhibition of apoptosis PDK and PKB

• The same hormone can active two different types of receptors (epinephrine can bind beta and alpha
adrenergic receptors) on different cells resulting in different responses
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