signalling secondmessengers 2019 · Endocrine – paracrine - autocrine Chemical synapsis Electric...
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2019.09.11. 1 Cell siganlling – second messenger systems (introduction) Learning objective: 7. 11.09.2019. Regulation of the cellular functions Types of the intercellular communications: Endocrine – paracrine - autocrine Chemical synapsis Electric synapsis/gap junctions Chemical signaling molecules („primary messengers”) : Hormones Neurotransmitters Local chemical signals (paracrine substances): Cytokines, inflammatory mediators, growth factors, antigenes etc. Membrane receptors: Specific binding of mediator substances – activation (conformation change) – signalisation process Consequence of the receptor activation I.: Changes in the membrane potential: • Ligand-gated ion channels (ionotropic receptors) • functional coupling with ion channels (metabotropic receptors)
Transcript of signalling secondmessengers 2019 · Endocrine – paracrine - autocrine Chemical synapsis Electric...
2019.09.11.
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Cell siganlling – second messenger systems (introduction)
Learning objective: 7. 11.09.2019.
Regulation of the cellular functions
Types of the intercellular communications:
Endocrine – paracrine - autocrine
Chemical synapsis
Electric synapsis/gap junctions
Chemical signaling molecules („primary messengers”) :
Hormones
Neurotransmitters
Local chemical signals (paracrine substances):
Cytokines, inflammatory mediators, growth factors, antigenes etc.
Membrane receptors:
Specific binding of mediator substances – activation (conformation change)
– signalisation process
Consequence of the receptor activation I.:
Changes in the membrane potential:
• Ligand-gated ion channels (ionotropic receptors)
• functional coupling with ion channels (metabotropic receptors)
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Types of the intercellular communication processes(primary messengers and their receptors)
Consequence of the receptor activation II:
Activation of second messenger systems - intracellular signal transduction
Functions:
Functional connection between the activated receptor and effector (enzymes,
ion channels, transporters, motor elements, regulator proteins etc.) molecules
Second messenger systems:
Intracellular Ca2+ transients
cAMP (cGMP): adenylate-(guanylate-) cyclase – protein kinase A system
Phosphoinositol: PIP2 - phospholipase C – protein kinase C system
Tyrosine kinases: growth factors, insulin
Nitric oxide (NO): NO receptors - guanylate cyclase
Arachidonic acid – phopholipase A
Cytoplasmic/nuclear receptors: steroid hormones, T3/T4, eicosanoids, NO
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What are the common traits of these systems?
Specificity: selective ligand binding to the receptors
selective phosphorylation by protein kinases
(Specific binding sites, phosphorylation sites: Ser, Thr or Tyr)
but: protein kinases can activate or inactivate different proteins (divergence)
one protein can be regulated by different protein kinases or other second
messenger systems (convergence)
Overlaps and bidirectional interactions between different messenger systems
(inhibition or stimulation, feed-back/feed-forward; regulatory networks)
Amplification: Cascade systems – adenylate cyclase, protein kinases can activate
large number of downstream elements – auto-amplification
„chain reaction”
Safety factors: The signal must be limited both spatially and temporally
– intrinsic regulatory mechanisms („breaks”)
e.g.:
Adenylate cyclase – G-Protein: GTP hydrolysis limits G-prot. activity
cAMP – Phosphodiesterase inactivates cAMP
Ca2+ - pumps maintain resting plasma Ca2+ concentration at low level
Plasma concentrations of the hormones are in a very low pmol/nmol/ low micromolar range
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Signal amplification – cascade mechanism
Intracellular calcium as a second messenger (ion)
www.cellsignallingbiology.org
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www.cellsignallingbiology.org
„Modular” composition of the calcium-signalling
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Functional model of calmodulin and other intracellular Ca-binding proteins
VOC: Voltage Operated Calcium Channel; CCE: Capacitive Calcium Entry; CaM: Calmodulin; MLCK Myosin
Light Chain Kinase
Example I: Calcium – calmodulin system (smooth muscle cells)
[Ca2+]ic ~10-7
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Measurement of the Ca-transients – Ca-sensitive fluorescent dyes (e.g.: FURA-2)
G-proteins and G-protein coupled receptors (GPCRs)
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Connections of heterotrimer G-proteins to different intracellular signal pathways
www.cellsignallingbiology.org
G-protein coupled receptors (GPCRs) – adenylyl cyclase / protein kinase A
pathway
www.cellsignallingbiology.org
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Adenylyl cyclase- cAMP – proteinkinase-A system II.
www.cellsignallingbiology.org
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GPCRs – phospholypase C – DAG/InsP3 – Protein Kinase C pathway
www.cellsignallingbiology.org
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(cAMP) - System
