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Ca
+
Tropomyosin
alpha-1 chain
Tropomyosin
beta chain
Beta-1
adrenergic
receptor
Beta-2
adrenergic
receptor
Adenylate
cyclase type 9
cAMP-dependent
protein kinase
catalytic
subunit beta
cAMP-dependent
protein kinase
catalytic
subunit gamma
cAMP-dependent
protein kinase
type I-alpha
regulatory
subunit
cAMP-dependent
protein kinase
type I-beta
regulatory
subunit
cAMP-dependent
protein kinase
type II-alpha
regulatory
subunit
cAMP-dependent
protein kinase
type II-beta
regulatory
subunit
Myosin light
chain kinase,
smooth muscle
cAMP-dependent
protein kinase
type I-alpha
regulatory
subunit
Voltage-
depenent L-type
calcium channel
Voltage-
depenent L-type
calcium channel
Voltage-
depenent L-type
calcium channel
Ryanodine
receptor 2
Myosin light
chain 3
Myosin LC-P
Actin,
cytoplasmic 1
Sodium/calcium
exchanger 1
Voltage-gated
T-type calcium
channel (ICaT)
Voltage-gated
T-type calcium
channel (ICaT)
Voltage-
dependent
P/Q-type
calcium channel
subunit
alpha-1A
Voltage-
dependent
L-type calcium
channel subunit
beta-1
Voltage-
dependent
calcium channel
subunit
alpha-2/delta-2
Myosin light
chain kinase,
smooth muscle
Serine/threonine-
protein
phosphatase
PP1-beta
catalytic
subunit
Calmodulin-1
Sarcoplasmic/endoplasmic
reticulum
calcium ATPase
2
Calmodulin-1
cAMP-dependent
protein kinase
catalytic
subunit alpha
Timolol
Timolol
cAMP
Ca
+
Ca
+
Ca
+
Ca
+
Na
+
Na
+
Ca
+
Ca
+
Ca
+
Ca
+
ATP
PP
i
ATP
H
2
O
Ca
+
ADP
P
i
Ca
+
Magnesium
Magnesium
Calcium
Manganese
Ca
+
Ca
+
Troponin
Troponin
G-protein
signalling
cascade
Muscle
Contraction
Muscle
Relaxation
Other
Intracellular
Signaling
Pathways
Muscle
Contraction
Cardiac Myocyte
Sarcoplasmic Reticulum
Calcium binding to troponin
displaces tropomyosin from
the myosin binding sites on
the actin filaments
Myosin, with an ADP and
phosphate attached, binds to
actin to form a cross
bridge. Myosin performs a
powerstroke, drawing the
actin filaments together.
Many actin filaments pulled
together at the same time
leads to muscle contraction.
Actin Filament
Myosin Filament
Single Sarcomere Functioning
Unit
The beta-1 adrenergic
receptor is coupled to and
activates the G-protein
signalling cascade.
The G-protein signalling
cascade activates protein
kinase which activates
calcium channels on the
membrane, resulting in
calcium influx.
Calcium activates the
ryanodine receptor on the
sarcoplasmic reticulum.
Time
Membrane potential (mV)
-40mV (threshold)
Pacemaker Action Potential
Phase 0- depolarization
Phase 3- repolarization
Phase 4-spontaneous
depolarization
With propranolol
Without propranolol
Timolol, by antagonizing
beta-1 adrenergic receptors,
decreases intracellular
Ca2+. Phase 4 spontaneous
depolarization is Ca2+
dependent, therefore
propranolol decreases the
slope of phase 4, increasing
the time it takes for
threshold to be reached and
thus slows heart rate
Cytosol
Since calcium is linked to
activation of muscle
contraction. Reducing
cytosolic calcium levels
reduces muscle contraction
Timolol enters the
bloodstream and once it
reaches the heart, it
antagonizes the beta-1
adrenergic receptor on the
cell membrane of myocytes
such that epinephrine
stimulation of the heart is
reduced.
T-tubule
Activation of
beta-2adrenergic recepotrs
activates the Gs signaling
cascade leading to increased
levels of cAMP and
activation of protein kinase
A.
Timolol activates
beta-2-adrenergic receptors
in the smooth muscle of the
respiratory airways
Accumulation of myosin LC
leads to increased
relaxation of the airway
smooth muscles
Myosin light chain kinase
phosphorylates myosin light
chain, whereas myosin light
chain phosphatase
dephosphorylates myosin LC-P
Myosin LC-P interacts with
actin to produce smooth
muscle contraction. Since
there are low levels of
myosin LC-P, contraction is
inhibited
Caclium usually binds to
calmodulin to activate
myosin light chain kinase.
Since Ca2+ levles are low,
activation of myosin light
chain kinase is reduced.
PKA may also phosphorylate
Gq-coupled receptors leading
to a cascade of
intracellular signals which
reduce intracellular Ca2+
PKA inactivates myosin light
chain kinase by
phosphorylating it
Mitochondria
Calcium
TPM1
TPM2
ADRB1
ADRB2
ADCY9
PRKACB
PRKACG
PRKAR1A
PRKAR1B
PRKAR2A
PRKAR2B
MYLK
PRKAR1A
CACNA1C
CACNA2D2
CACNB1
RYR2
MYL3
MYL3
ACTB
SLC8A1
CACNA1H
CACNA1G
CACNA1A
CACNB1
CACNA2D2
MYLK
PPP1CB
CALM1
ATP2A2
CALM1
PRKACA
Timolol
Timolol
cAMP
Calcium
Calcium
Calcium
Calcium
Sodium
Sodium
Calcium
Calcium
Calcium
Calcium
Adenosine
triphosphate
Pyrophosphate
Adenosine
triphosphate
Water
Calcium
Adenosine
diphosphate
Phosphate
Calcium
Calcium
Calcium
Troponin
Troponin
G-protein
signalling
cascade
Muscle
Contraction
Muscle
Relaxation
Other
Intracellular
Signaling
Pathways
Muscle
Contraction