3. Ca2+
• One of the most important second messengers is Ca++.
• In general, Ca++ enters the cytosol through gated ion channels in the
plasma membrane and/or the endoplasmic reticulum.
• The ion channels in the plasma membrane, for example, could be
voltage-gated, ligand-gated or temperature-gated.
• Those in the endoplasmic reticulum typically are gated by IP3.
• Once in the cytosol, the Ca++ typically binds to a small protein,
calmodulin.
• Once four Ca++ bind to calmodulin, it activates specific proteins inside
the cell, such are certain protein kinases.
• Skeletal and cardiac muscle have another Ca++ binding protein termed
troponin. However, it is related structurally to calmodulin
6. Ca2+
• As the functions of IP3 and DAG indicate, calcium ions are also important
intracellular messengers.
• In fact, calcium ions are probably the most widely used intracellular messengers.
• In response to many different signals, a rise in the concentration of Ca2+ in the
cytosol triggers many types of events such as
• muscle contraction
• exocytosis, e.g.,
– release of neurotransmitters at synapses (and essential for the long-term
synaptic change)
– secretion of hormones like insulin
• activation of T cells and B cells when they bind antigen with their antigen
receptors.
• adhesion of cells to the extracellular matrix
• apoptosis
• a variety of biochemical changes mediated by Protein Kinase C.
7. Ca2+
• Normally, the level of calcium in the cell is very
low (~100 nM).
• There are two main depots of Ca2+ for the cell:
1. The extracellular fluid (ECF — made from blood)
• where the concentration is ~ 2 mM or 20,000 times
higher than in the cytosol
2. The endoplasmic reticulum ("sarcoplasmic"
reticulum in skeletal muscle).
8. Ca2+
• However its level in the cell can rise
dramatically as follows:
1. when channels in the plasma membrane
open to allow it in from the extracellular
fluid or
2. from depots within the cell such as the
endoplasmic reticulum and mitochondria.
9. Ca2+
Getting Ca2+ into (and out of) the cytosol:
1. Voltage-gated channels
– open in response to a change in membrane potential, e.g. the
depolarization of an action potential;
– These are found in excitable cells:
• skeletal muscle
• smooth muscle
• neurons. When the action potential reaches the presynaptic
terminal, the influx of Ca2+ triggers the release/exocytosis of the
neurotransmitter.
• the taste cells that respond to salt.
2. Receptor-operated channels
These are found in the post-synaptic membrane and open when they
bind a neurotransmitter.
• G-protein-coupled receptors- These are not channels but they trigger a
release of Ca2+ from the endoplasmic reticulum. They are activated by
various hormones and neurotransmitters.
12. Neuron A (transmitting) to neuron B (receiving)
1. Mitochondrion
2. synaptic vesicle with neurotransmitters
3. Autoreceptor
4. Synapse with NT released (serotonin)
5. Postsynaptic receptors activated by NT (induction of a
postsynaptic potential)
6. Calcium channel
7. Exocytosis of a vesicle
8. Recaptured neurotransmitter
13. Ca2+
Ca2+ ions are returned to the ECF by active
transport using:
1. an ATP-driven pump called a Ca2+ ATPase
2. to the endoplasmic (and sarcoplasmic)
reticulum using another Ca2+ ATPase.
14. Ca2+
How can such a simple ion like Ca2+ regulate so
many different processes?
Some factors at work:
• localization within the cell- released at one spot
• the T-system— spread throughout the cell
• by the amount released - amplitude modulation
• by releasing it in pulses of different frequencies -
frequency modulation
15. HORMRONES THAT USE CA2+/ IP3 SYSTEM:
• Epinephrine and norepinephrine
• angiotensin II
• antidiuretic hormone
• gonadotropin-releasing hormone
• thyroid-releasing hormone.
• The effects of Ca2+ is also remarkable: it cooperates with DAG in activating
PKC
• and can activate CaM kinase pathway, in which calcium modulated protein
calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and
activates CaM kinase II,
• which has unique ability to increase its binding affinity to CaM by
autophosphorylation, making CaM unavailable for the activation of other
enzymes.
• The kinase then phosphorylates target enzymes, regulating their activities.
• The two signal pathways are connected together by Ca2+-CaM, which is also
a regulatory subunit of
• adenylyl cyclase and phosphodiesterase in cAMP signal pathway.
18. Recommended Adequate Intake of Calcium
Age Calcium (mg/day)
0–6 months 210
7–12 months 270
1–3 years 500
4–8 years 800
9–18 years 1300
19–50 years 1000
51+ years 1200
