This document discusses second messengers and signal transduction. It defines second messengers as molecules that relay signals from cell surface receptors to target molecules inside the cell. It describes several types of second messengers including cyclic nucleotides, calcium, lipid derivatives, and gases. It discusses specific second messengers like cAMP, cGMP, IP3, DAG, and nitric oxide. It also reviews different classes of ion channels and protein kinases that are involved in signal transduction.

1. Dr Manjuprasad
Moderator: Dr Vijayalaxmi M.K

2.  They are the molecules which relay signals
from receptors on cell surface to target
molecules inside the cytoplasm or nucleus.
 Discovered by Earl Wilbur Sutherland in 1971

3. Types:
• Hydrophobic: eg; DAG, phosphotidyl inositol
• Hydrophilic: eg; cAMP, cGMP, IP3 & calcium
• Gases : eg; NO, CO, H2S

4.  Synthesized, released & broken down again
in specific reactions by enzymes.
 Can be stored & quickly released when
needed
 Production, release and destruction can be
localised

5.  Cyclic nucleotides: cAMP
cGMP
 Calcium
 Lipid derivatives: IP3
DAG

6. cAMP
 Synthesized from ATP
 Regulates some ion channels as ligands
 Regulates kinase
which phosphorylates substrates
- increases glycogen breakdown
- decrease glycogen synthesis
-increase cardiac beat strength
Eg: Adrenaline, Glucagon, LH

10. cGMP
 Made from GTP
 Membrane bound or soluble
 Can act as a receptor
 Regulates some ion channels and protein kinases
 Important in smooth muscle relaxation and visual
system
 Eg: ANP, NO

11. Calcium:
 At rest maintains low cytoplasmic
concentration
 Channels open with ligand gated or voltage
gateing
 Actions: muscle contraction
neuronal transmission
cellular motility
cell growth

12. Inositol tri-phosphate
 Hydrophilic
 Agonist for internal calcium channel
 [Ca++]i rises
 Multiple effects through Ca++-binding
proteins

13. Diacylglycerol
 Hydrophobic
 Targets PKC (a kinase)
 PKC requires Ca++ and DAG

15. Types:
• Voltage gated
eg: Lignocaine, verapamil
• Ligand gated
eg: gabapentine, nicotine

16.  Multiple isoforms
 Generation of action potential
Sodium channels
 One α and 2β
 α subunit has 4 domains- sodium ion
selective pore forming pseudo tetramer
 Β subunit span the membrane once

17.  Each domain has 6 membrane spanning
helices (S1-S6)
 Extracellular loop S5 & S6 or pore forming
loop dips back into the pore
 Provides selective filter for sodium ions
 S4 of each domain surrounding the pore
contain charged amino acids that forms the
voltage sensor
 Cause conformational change in pore at more
positive voltage leading to opening of pore

19. Calcium channel
 This has a large α subunit (4 domains & 6
membrane spanning helices),
 3 regulatory subunits ie β,δ and γ
 Types:
 L-Type- long lasting
found in Skeletal muscle, smooth muscle, bone,
cardiac myosites and dendrites

20.  P-type (purkinje)
Purkinje neurons in the cerebellum / Cerebellar
granule cells
 N-type (neuronal)
Throughout the brain and peripheral nervous system
 R-type (residual)
Cerebellar granule cells, other neurons
 T-type (transient)
neurons, cells that have pacemaker activity, bone
(osteocytes)

21. Potassium channels:
 form channels as tetramers
 4 membrane spanning domains
 2 pore domain or leak potassium channels
-Dimers having 4 membrane spanning domains
surrounding 2 P loops
-Voltage insensitive
-Regulated by G proteins and H ions

22. • Activated by binding of ligand to a specific site
which causes conformational change in the
channel
• Specialized ion channels that are activated by
intracellular small molecules
Belong to Kv family
Eg:-cyclic nucleotide gated channel
-IP3 sensitive Ca channels
-5HT3 regulated channels

25.  Large proteins consisting of a single chain upto
1000 residues with single membrane spanning
helix
 Important role in-cell division
-growth
-differentiation
-inflammation
-tissue repair
-apoptosis
-immune response

26.  Receptor tyrosine kinases
 Serine/ threonine kinases
 Cytokine receptors

27.  Insulin, EGF, PDGF, NGF, FGF, VEGF
 Have a single polypeptide chain except for insulin
receptor
 Extracellular cysteine rich residues, short
transmembrane domain and intracellularly
containing one tyrosine kinase domains

29.  lack intrinsic enzyme activity. When
occupied, they associate with, and activate,
a cytosolic tyrosine kinase, such as Jak (the
Janus kinase)
 for these receptors include cytokines such as
interferons and colony-stimulating factors
involved in immunological responses.

31.  Ligand binding -- dimerises
 Phosphorylation of kinase domains
 Activated receptor  phosphorylates smad
 Dissociation from receptor
 Association with transcription factors and
gene regulation

32.  There are also inhibitory smads
Compete with phosphorylated smads to terminate
signalling
( S6 & S7 )

33.  Expressed in haematopoetic cells
 Related to innate immunity
 Structure is similar to kinase linked receptors
 Ligands- peptidoglycans, lipopolysaccharides,
and viruses
 Activation produces an inflammatory response

34.  These are ligand activated transcription
factors that transduce signals by modifying a
gene transcription
 Present in soluble phase become mobile in
presence of ligand and translocate from
cytoplasm to nucleus
 RXR dwell mainly in nuclear compartment

35.  Type 1:Receptors of steroid harmones
 Eg: estrogen, progesterone, testosterone
 Type 2:ligands present in cytoplasm to some
extent
 Eg: PPAR-that recognises fatty acids
 Type 3: characteristics of both 1 & 2
Imp role in endocrine signalling
Eg: thyroid harmone receptor, VitD receptor

38.  Myasthenia Gravis
 Testicular feminization syndrome
 Cystic Fibrosis
 SIDS
 Lambert eaton syndrome

39.  Goodman and Gilman – 12th edition
 Rang and Dales pharmacology 7th edition
 Textbook of medical pharmacology – Padmaja
udaykumar
 Uptodate.com
 Second messenger and signal transduction-
Dr Tim Bloom