Transcript JPEMDIASOR

Ion channels in the regulation of smooth muscle tone
Dr. Janos Pataricza
Department of Pharmacology and Pharmacotherapy
University of Szeged
1st of December , 2015
Content
 Regulation of smooth muscle contraction
 Some important ion channels and the tone of the smooth muscle
 K+ channels and vascular smooth muscle tone
 Cl- channels and vascular smooth muscle tone
-Possible relationships among voltage-dependent Ca2+ channels, ryanodine-sensitive Ca2+release (RyR) channels, large-conductance Ca2+-sensitive K+ (BKCa) channels, and Ca2+- a
activated Cl− (ClCa) channels to regulate smooth muscle contractility
 Ion channels in bronchial smooth muscle cells
 Involvement of ion channels in the regulation of cholinergic excitation in gastrointestinal tract
 Ion channels in the urinary tract
 Ion channels in the regulation of uterinal smooth muscle tone
-Strech-activated TREK-1, a type of two-pore K+ channels (K2P) also regulates myometrial tone
-Pregnancy, hypoxia and K+ ion channels
-Subfamily members of voltage dependent K+ channels (Kv7 and Kv11) in the regulation of uterinal tone
 Transient receptor potential channels (TRPC) in smooth muscle cells - link to intracellular signaling
 A crosstalk between the plasma membrane and sarcoplasmic reticulum involving Ca2+ and
K+ channels in smooth muscle cells
-Surface coupling between junctional sarcoplasmic reticulum (SR) and plasma membrane: leaflets of SR
and cell membranes are separated by an 12- to 20-nm gap
-Possible mechanisms of action of PKA/PKG and PKC on Ca2+sparks, BKCa channels, and
SR Ca2+-ATPase in arterial smooth muscle cells
 Endothelial nitric oxide influence the tone through modulation of ion channels in smooth muscle cell
of human umbilical artery
 Some basic properties of ionic regulation of smooth muscle tone
 Current research
Regulation of smooth muscle contraction
Webb RC, Advan in Physiol Edu 2003;27:201-206
Some important ion channels and vascular smooth muscle tone
Jackson WF, Hypertension. 2000;35:173-178
Inward rectifier K channel (KIR) ATP-sensitive K channel, (KATP), voltage dependent K channel (KV), big conductance
calcium activated K channel (BKCa), store-operated calcium channel (SOCC), stretch-activated K channel (SACC)
K+ channels and vascular smooth muscle tone
Jackson WF, Hypertension. 2000;35:173-178
Cl− channels and vascular smooth muscle tone
Jackson WF, Hypertension. 2000;35:173-178
Possible relationships among voltage-dependent Ca2+channels, ryanodinesensitive Ca2+-release (RyR) channels, large-conductance Ca2+-sensitive
K+(BKCa) channels, and Ca2+-activated Cl− (ClCa) channels to regulate
smooth muscle contractility.
JaggarJH et al., Am J Physiol Cell Physiol 2000;278:C235-C256
Ion channels in bronchial smooth muscle cells
Perez-Zoghbi JF et al, Pulm Pharmacol Ther. 2009 ;22(5):388-97
Find:
Receptor-operated Ca2+ influx or channels (ROC)
Store-operated Ca2+ entry or channels (SOC)
Calcium-activated potassium channels (KCa1.1, KCa3.1)
Voltage-dependent Ca2+ channels (VDC)
Stretch-activated channels (SA) are directly gated by physical stimuli
Involvement of ion channels in the regulation of cholinergic
excitation in gastrointestinal tract
Koh SD, Rhee PL J Neurogastroenterol Motil. 2013;19(4):426-32.
Possible post-junctional mechanisms responsible for cholinergic excitation. Acetylcholine (ACh) is
coupled to Gq/11 protein and activates conductance(s) through inositol 1,4,5-triphosphate receptor (IP3R)
in interstitial cells of Cajal (ICC) and smooth muscle cells (SMC). ACh might also be coupled to
G12/13 protein and activate Rho-Kinase (RhoK) pathway to induce contraction in SMC. ER, endoplasmic
reticulum; PLC, phospholipase C; DAG, diacyl glycerol; PKC, protein kinase C; CaCC, Ca2+-activated Cl- channels;
NSCC, non-selective cation channels; GJ, gap junction; MLCP, myosine light chain phosphatase.
Ion channels in the urinary tract
Kyle BD,Channels (Austin). 2014;8(5):393-401
urinary bladder
urethra
KATP, ATP-sensitive K+ channel;
BKCa, large conductance, Ca2+-activated K+ channel;
Kv, voltage-gated K+ channel;
K2P, 2-pore domain K+ channel;
IKCa, intermediate conductance K+ channel;
SKCa, small conductance K+ channel;
VGCC, voltage-gated Ca2+ channel;
CaCC, Ca2+-activated Cl− channel.
Ion channels in the regulation of uterinal smooth muscle tone
Brainard AM, Semin Cell Dev Biol. 2007;18(3):332-9.
Big conductance calcium activated K+ channel (BKCa), small conductance calcium activated K+ channel (SK3), ATPsensitive K+ channel (KATP) as a subtype of inward rectifier K+ channels (Kir), voltage dependent K+ channel (Kv)
Strech-activated TREK-1, a type of two-pore K+ channels
(K2P) also regulates myometrial tone
Buxton IL. et al, Acta Pharmacol Sin. 2011;32(6):758-64
Pregnancy, hypoxia and K+ ion channels
Zhu R et al. Curr Vasc Pharmacol. 2013;11(5):737-47.
Subfamily members of voltage dependent K+ channels
(Kv.7 and Kv.11) in the regulation of uterinal tone
Greenwood IA, Tribe RM.Exp Physiol. 2014;99(3):503-9
Left-hand panel shows that open K+ channels result in membrane hyperpolarization that indirectly limits
the opening of voltage-dependent calcium channels shown in blue. This results in a less contracted
smooth muscle. In the right-hand panel, the potassium channels are non-functional due to blockade,
loss-of-function mutations or trafficking defects. This leads to membrane depolariziation, and the open probability
of the calcium channels increases. The concomitant influx of calcium contributes to smooth muscle contraction.
Transient receptor potential channels (TRPC) in smooth
muscle cells – link to intracellular signaling
Gonzalez-Cobos JC1, Trebak M, Front Biosci (Landmark Ed). 2010 Jun 1;15:1023-3
The engagement of a vasoactive compound/growth factor receptor in vascular smooth muscle cells leads to the activation of
phospholipase C (PLC) which catalyzes the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) into two intracellular
second messengers, the Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). IP3-mediated Ca2+ store depletion activates
store-operated Orai1 channels in a mechanism dependent on STIM1 aggregation and translocation into areas of close SR-PM
contacts. The role of TRPC channels in mediating SOC channels remains to this day a highly contentious issue. All TRPC are
Activated by mechanisms downstream of PLC; TRPC3/6/7 have been shown to be activated by DAG in a PKC independent manner
while TRPC1/4/5 exact mechanisms of activation via membrane receptors is still unclear and seems to involve PIP2 breakdown and
Ca2+. Na+entry through nonselective TRPC channels has been proposed to couple to activation of Ca2+ entry either through the
Na+/Ca2+ exchanger (NCX) or via depolarization and subsequent activation of L-type Ca2+ channels. Increasing evidence supports
a signaling paradigm in which Ca2+ signals mediated by specific TRPC isoforms are able to activate transcription factors in smooth
A crosstalk between the plasma membrane and sarcoplasmic
reticulum involving Ca2+ and K+ channels in smooth muscle cells
Jaggar JH. et al. Am J Physiol Cell Physiol 2000;278:C235-C256
Surface coupling between junctional sarcoplasmic reticulum
(SR) and plasma membrane: leaflets of SR and cell membranes
are separated by an 12- to 20-nm gap.
Jaggar JH et al. Am J Physiol Cell Physiol 2000;278:C235-C256
Possible mechanisms of action of PKA/PKG and PKC on
Ca2+sparks, BKCa channels, and SR Ca2+-ATPase in arterial
smooth muscle cells.
Jaggar JH. et al. Am J Physiol Cell Physiol 2000;278:C235-C256
Endothelial nitric oxide influence the tone through modulation
of ion channels in smooth muscle cell of human umbilical artery
Martin P. et al., Reprod Sci. 2014 April; 21(4): 432–441.
NO,nitric oxide; KV, voltage-dependent K+ channels (different subfamilies); BKCa, big conductance, voltageand Ca2+-sensitive K+ channel; SKCa, small conductance Ca2+-sensitive K+ channels; K2P, 2-pore domains K+ channels;
KIR, inward rectifier K+ channels. Intermediate conductance Ca2+-sensitive K+ channels (IKCa), and
ATP-sensitive K+ channels (KATP) are not include because the evidence about their presence in HUA is either weak (KATP)
or altogether not present in the literature (IKCa). 1/ basal tone, 2/ agonist-induced contraction 3/ regulation by endothelium
Some basic properties of ionic regulation of smooth
muscle tone
 Smooth muscle function is mainly regulated by the voltage
operated (or dependent, or gated) calcium channels (VOCC or
VDCC or VDC or VGCC)
 Typically, a large majority of other ion channels modulate
membrane potential that regulates VOCC
 Most types of smooth muscle cells are „electrically silent”- in
contrast to nerves or skeletal muscles-; no action potential is
generated (resting membrane potential is about -50 mV)
 Ion channels maintain resting (basal) tension, modulate
agonist-induced contractions and vasodilations by
endothelial/interstitial cell-derived factors
Current research
 Research focuses mainly on K+ channels in the regulation of
smooth muscle tone of different organs (vascular, bronchial,
uterinal) – an exception may be the gastrointestinal tract
 A typical ion channel is still considered to be a receptor without
cellular effector, however, some ion channels reveal a complex
interaction with intracellular signaling mechanisms. This ‘crosstalk’
may lead to changes of cellular phenotype in addition to modify an
immediate change in tone of smooth muscle cells (see TRPC
channels)
Questions
1/ Which ion is mainly responsible for the contraction of a
smooth muscle cell? (Ca++)
2/ List some important ion channels – other than Ca2+
channel- that play roles in regulating the tone of smooth
muscle cells! (K+ channels, Cl- channels, Store-operated
channels, Stretch-activated channels)
3/ How K+ and Cl- channels regulate the tone of smooth
muscle cells? (activation of K+ channels relaxes, that of Clchannels contracts smooth muscles via modulation of
membrane potential)
4/ List some known common ion channels that regulate the
tone of bronchial, urinary and uterinal smooth muscles!
(Ca2+ channels, K+ channels, Store-operated channels,
Stretch-activated channels)
Questions
5/ Which ion channels appear to be important in cholinergic
excitation of gastrointestinal smooth muscles? (Calciumactivated Cl- channels, Non-selective cation channels)
6/ What are K2P channels and which type of tissue is
known to be regulated by these channels? (uterinal smooth
muscle, in another word: myometrial tissue)
7/ How may pregnancy affect the function of K+ channels?
(activates K+ channels– relaxation of the uterus)
8/ What kind of K+ ion channel is involved in a ‘crosstalk’
between plasma membrane and sarcoplasmic reticulum of
smooth muscle cells? (BKCa)
9/ How do protein kinases influence K+ channels in smooth
muscles according to our present knowledge?
(PKA and PKG activate, PKC inhibits)