Smooth Muscle Contraction (Homo sapiens)

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11, 95, 6, 810-123, 710, 114, 810-1210, 11cytoplasmic vesicle lumencytosolCALD1 TPM2 p-S19-MYL12A p-S20-MYL6 p-S20-MYL6 ACTA2 ITGB5 ITGA1 Calcium Bound MyosinActin ComplexCAV3PXN CAV3:TRIM72:DYSF:ANXA6:ANXA1:ANXA2p-S16-MYLPF p-S21-MYL5 MYL7 p-S141,T402-PAK2 p-S20-MYL9 TPM4 TRIM72 p-S20-MYL6 TPM3 p-S23-MYL7 VCL p-S23-MYL7 SORBS1 p-S23-MYL7 MYL12B DYSFANXA2ACTA2 MYLK:Ca2+:CALM1MYL6B p-S20-MYL9 p-S21-MYL5 VCL TPM2 p-S20-MYL6B MYH11 ADP:Calcium BoundMyosin ActinComplexp-S144,T423-PAK1 p-S23-MYL7 LMOD1 ATP:Calcium BoundMyosin ActinComplexp-S21-MYL5 ADPMYL5 PiCa2+TLN1 PXN Ca2+ ITGB5 ANXA6TPM2 ITGB5 p-T19,S20-MYL12B CALM1p-S23-MYL7 MYH11 TPM4 CALD1 CAV3:TRIM72:DYSFp-S20-MYL9 ITGA1 ATP ITGA1 CALM1:4xCa2+TPM1 p-S16-MYLPF TPM4 ATP Bound SmoothMuscle MyosinComplexp-S21-MYL5 Ca2+p-S,T-MYL10 PXN TPM2 p-S16-MYLPF MYL10 p-S,T-MYL10 TPM1 ITGB5 SORBS1 PhosphorylatedSmooth MuscleMyosin Light Chainp-S21-MYL5 MYH11 SORBS1 ANXA1p-S20-MYL9 SORBS3 p-S16-MYLPF p-S20-MYL9 TPM3 CALD1 p-S19-MYL12A DYSF TLN1 ACTG2 p-S,T-MYL10 p-S19-MYL12A p-S20-MYL6 CALM1 p-S19-MYL12A ACTG2 p-S19-MYL12A p-S,T-PAK1,2CALD1 TLN1 MYLK(1-1914) p-T19,S20-MYL12B p-S,T-MYL10 TRIM72 ATPp-S20-MYL6B p-S20-MYL6B LMOD1 MYLPF p-S16-MYLPF MYL12A MYL6 p-T19,S20-MYL12B p-S20-MYL6B SORBS3 SORBS1 TPM4 MYL9 ITGA1 VCL p-T19,S20-MYL12B LMOD1 p-S,T-MYL10 p-S23-MYL7 SORBS3 p-T19,S20-MYL12B Ca2+ TLN1 PXN ACTG2 TPM3 ACTA2 Ca2+ p-S20-MYL6 p-T19,S20-MYL12B VCL MYH11 CAV3 Inactive MyosinActin ContractileComplexTPM3 p-S,T-MYL10 CAV3 p-S20-MYL6B Smooth Muscle MyosinLight ChainMYH11 TRIM72Ca2+ ANXA6 ADP p-S20-MYL6B DYSF MYLK(1-1914)ATP TPM1 CALM1 TPM1 SORBS3 ANXA2 p-S16-MYLPF p-S21-MYL5 Ca2+ ANXA1 ADPp-S19-MYL12A LMOD1 p-S20-MYL6 ACTG2 ACTA2 p-S20-MYL9 ATP213


Layers of smooth muscle cells can be found in the walls of numerous organs and tissues within the body. Smooth muscle tissue lacks the striated banding pattern characteristic of skeletal and cardiac muscle. Smooth muscle is triggered to contract by the autonomic nervous system, hormones, autocrine/paracrine agents, local chemical signals, and changes in load or length.

Actin:myosin cross bridging is used to develop force with the influx of calcium ions (Ca2+) initiating contraction. Two separate protein pathways, both triggered by calcium influx contribute to contraction, a calmodulin driven kinase pathway, and a caldesmon driven pathway.
Recent evidence suggests that actin, myosin, and intermediate filaments may be far more volatile then previously suspected, and that changes in these cytoskeletal elements along with alterations of the focal adhesions that anchor these proteins may contribute to the contractile cycle.
Contraction in smooth muscle generally uses a variant of the same sliding filament model found in striated muscle, except in smooth muscle the actin and myosin filaments are anchored to focal adhesions, and dense bodies, spread over the surface of the smooth muscle cell. When actin and myosin move across one another focal adhesions are drawn towards dense bodies, effectively squeezing the cell into a smaller conformation. The sliding is triggered by calcium:caldesmon binding, caldesmon acting in an analogous fashion to troponin in striated muscle. Phosphorylation of myosin light chains also is involved in the initiation of an effective contraction.

View original pathway at:Reactome.


Pathway is converted from Reactome ID: 445355
Reactome version: 66
Reactome Author 
Reactome Author: Gillespie, Marc E

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Ontology Terms



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  1. Webb RC.; ''Smooth muscle contraction and relaxation.''; PubMed Europe PMC
  2. Qualmann B, Kessels MM.; ''New players in actin polymerization--WH2-domain-containing actin nucleators.''; PubMed Europe PMC
  3. Marston SB, Redwood CS.; ''The molecular anatomy of caldesmon.''; PubMed Europe PMC
  4. Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown RH.; ''The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.''; PubMed Europe PMC
  5. Roostalu U, Strähle U.; ''In vivo imaging of molecular interactions at damaged sarcolemma.''; PubMed Europe PMC
  6. Lennon NJ, Kho A, Bacskai BJ, Perlmutter SL, Hyman BT, Brown RH.; ''Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing.''; PubMed Europe PMC
  7. Morgan KG, Gangopadhyay SS.; ''Invited review: cross-bridge regulation by thin filament-associated proteins.''; PubMed Europe PMC
  8. Cai C, Weisleder N, Ko JK, Komazaki S, Sunada Y, Nishi M, Takeshima H, Ma J.; ''Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin.''; PubMed Europe PMC
  9. Hathaway DR, Adelstein RS.; ''Human platelet myosin light chain kinase requires the calcium-binding protein calmodulin for activity.''; PubMed Europe PMC
  10. Kumar CC, Mohan SR, Zavodny PJ, Narula SK, Leibowitz PJ.; ''Characterization and differential expression of human vascular smooth muscle myosin light chain 2 isoform in nonmuscle cells.''; PubMed Europe PMC
  11. Cavaillé F, Janmot C, Ropert S, d'Albis A.; ''Isoforms of myosin and actin in human, monkey and rat myometrium. Comparison of pregnant and non-pregnant uterus proteins.''; PubMed Europe PMC
  12. Mohammad MA, Sparrow MP.; ''The distribution of heavy-chain isoforms of myosin in airways smooth muscle from adult and neonate humans.''; PubMed Europe PMC
  13. Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMed Europe PMC


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101613view11:48, 1 November 2018ReactomeTeamreactome version 66
101149view21:34, 31 October 2018ReactomeTeamreactome version 65
100677view20:07, 31 October 2018ReactomeTeamreactome version 64
100227view16:52, 31 October 2018ReactomeTeamreactome version 63
99778view15:18, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93385view11:22, 9 August 2017ReactomeTeamreactome version 61
86471view09:19, 11 July 2016ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ACTA2 ProteinP62736 (Uniprot-TrEMBL)
ACTG2 ProteinP63267 (Uniprot-TrEMBL)
ADP MetaboliteCHEBI:16761 (ChEBI)
ADP:Calcium Bound

Myosin Actin

ComplexR-HSA-445697 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ANXA1 ProteinP04083 (Uniprot-TrEMBL)
ANXA1ProteinP04083 (Uniprot-TrEMBL)
ANXA2 ProteinP07355 (Uniprot-TrEMBL)
ANXA2ProteinP07355 (Uniprot-TrEMBL)
ANXA6 ProteinP08133 (Uniprot-TrEMBL)
ANXA6ProteinP08133 (Uniprot-TrEMBL)
ATP Bound Smooth

Muscle Myosin

ComplexR-HSA-445789 (Reactome)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATP:Calcium Bound

Myosin Actin

ComplexR-HSA-445701 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
CALD1 ProteinQ05682 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAV3 ProteinP56539 (Uniprot-TrEMBL)
CAV3:TRIM72:DYSF:ANXA6:ANXA1:ANXA2ComplexR-HSA-5263623 (Reactome)
CAV3:TRIM72:DYSFComplexR-HSA-5263629 (Reactome)
CAV3ProteinP56539 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcium Bound Myosin Actin ComplexComplexR-HSA-445702 (Reactome)
DYSF ProteinO75923 (Uniprot-TrEMBL)
DYSFProteinO75923 (Uniprot-TrEMBL)
ITGA1 ProteinP56199 (Uniprot-TrEMBL)
ITGB5 ProteinP18084 (Uniprot-TrEMBL)
Inactive Myosin

Actin Contractile

ComplexR-HSA-445703 (Reactome)
LMOD1 ProteinP29536 (Uniprot-TrEMBL)
MYH11 ProteinP35749 (Uniprot-TrEMBL)
MYL10 ProteinQ9BUA6 (Uniprot-TrEMBL)
MYL12A ProteinP19105 (Uniprot-TrEMBL)
MYL12B ProteinO14950 (Uniprot-TrEMBL)
MYL5 ProteinQ02045 (Uniprot-TrEMBL)
MYL6 ProteinP60660 (Uniprot-TrEMBL)
MYL6B ProteinP14649 (Uniprot-TrEMBL)
MYL7 ProteinQ01449 (Uniprot-TrEMBL)
MYL9 ProteinP24844 (Uniprot-TrEMBL)
MYLK(1-1914) ProteinQ15746 (Uniprot-TrEMBL)
MYLK(1-1914)ProteinQ15746 (Uniprot-TrEMBL)
MYLK:Ca2+:CALM1ComplexR-HSA-445764 (Reactome)
MYLPF ProteinQ96A32 (Uniprot-TrEMBL)
PXN ProteinP49023 (Uniprot-TrEMBL)

Smooth Muscle

Myosin Light Chain
ComplexR-HSA-445770 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
SORBS1 ProteinQ9BX66 (Uniprot-TrEMBL)
SORBS3 ProteinO60504 (Uniprot-TrEMBL)
Smooth Muscle Myosin Light ChainComplexR-HSA-445793 (Reactome)
TLN1 ProteinQ9Y490 (Uniprot-TrEMBL)
TPM1 ProteinP09493 (Uniprot-TrEMBL)
TPM2 ProteinP07951 (Uniprot-TrEMBL)
TPM3 ProteinP06753 (Uniprot-TrEMBL)
TPM4 ProteinP67936 (Uniprot-TrEMBL)
TRIM72 ProteinQ6ZMU5 (Uniprot-TrEMBL)
TRIM72ProteinQ6ZMU5 (Uniprot-TrEMBL)
VCL ProteinP18206 (Uniprot-TrEMBL)
p-S,T-MYL10 ProteinQ9BUA6 (Uniprot-TrEMBL)
p-S,T-PAK1,2ComplexR-HSA-5668976 (Reactome)
p-S141,T402-PAK2 ProteinQ13177 (Uniprot-TrEMBL)
p-S144,T423-PAK1 ProteinQ13153 (Uniprot-TrEMBL)
p-S16-MYLPF ProteinQ96A32 (Uniprot-TrEMBL)
p-S19-MYL12A ProteinP19105 (Uniprot-TrEMBL)
p-S20-MYL6 ProteinP60660 (Uniprot-TrEMBL)
p-S20-MYL6B ProteinP14649 (Uniprot-TrEMBL)
p-S20-MYL9 ProteinP24844 (Uniprot-TrEMBL)
p-S21-MYL5 ProteinQ02045 (Uniprot-TrEMBL)
p-S23-MYL7 ProteinQ01449 (Uniprot-TrEMBL)
p-T19,S20-MYL12B ProteinO14950 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADP:Calcium Bound

Myosin Actin

ArrowR-HSA-445699 (Reactome)
ADP:Calcium Bound

Myosin Actin

R-HSA-445705 (Reactome)
ADPArrowR-HSA-445705 (Reactome)
ADPArrowR-HSA-445813 (Reactome)
ANXA1R-HSA-5263628 (Reactome)
ANXA2R-HSA-5263628 (Reactome)
ANXA6R-HSA-5263628 (Reactome)
ATP Bound Smooth

Muscle Myosin

mim-catalysisR-HSA-445699 (Reactome)
ATP:Calcium Bound

Myosin Actin

ArrowR-HSA-445700 (Reactome)
ATP:Calcium Bound

Myosin Actin

R-HSA-445699 (Reactome)
ATPR-HSA-445700 (Reactome)
ATPR-HSA-445813 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+R-HSA-445797 (Reactome)
CALM1R-HSA-74448 (Reactome)
CAV3:TRIM72:DYSF:ANXA6:ANXA1:ANXA2ArrowR-HSA-5263628 (Reactome)
CAV3:TRIM72:DYSFArrowR-HSA-5263633 (Reactome)
CAV3:TRIM72:DYSFR-HSA-5263628 (Reactome)
CAV3R-HSA-5263633 (Reactome)
Ca2+ArrowR-HSA-5263628 (Reactome)
Ca2+ArrowR-HSA-5263633 (Reactome)
Ca2+R-HSA-445704 (Reactome)
Ca2+R-HSA-74448 (Reactome)
Calcium Bound Myosin Actin ComplexArrowR-HSA-445704 (Reactome)
Calcium Bound Myosin Actin ComplexArrowR-HSA-445705 (Reactome)
Calcium Bound Myosin Actin ComplexR-HSA-445700 (Reactome)
DYSFR-HSA-5263633 (Reactome)
Inactive Myosin

Actin Contractile

R-HSA-445704 (Reactome)
MYLK(1-1914)R-HSA-445797 (Reactome)
MYLK:Ca2+:CALM1ArrowR-HSA-445797 (Reactome)
MYLK:Ca2+:CALM1mim-catalysisR-HSA-445813 (Reactome)

Smooth Muscle

Myosin Light Chain
ArrowR-HSA-445813 (Reactome)
PiArrowR-HSA-445699 (Reactome)
R-HSA-445699 (Reactome) Once ATP is bound, myosin, which is an ATPase, uses the energy from the cleavage of the terminal phosphate to pivot the myosin head back, away from the actin filamentous chain. This change in conformation "resets" the myosin molecule, leaving it ready to bind the actin filament once more and slide the myosin filament along the actin filament, continuing the contractile cycle.
R-HSA-445700 (Reactome) With the expulsion of ADP from the nucleotide binding pocket, ATP, if available will immediately bind.
R-HSA-445704 (Reactome) Caldesmon functions in an analogous fashion to troponin in striated muscle. Once calcium has entered the smooth muscle cell, calcium levels slowly rise. Caldesmon binds calcium, freeing tropomyosin, allowing the tropomyosin to move exposing the active sites on actin for myosin binding.
R-HSA-445705 (Reactome) As soon as the actin and myosin filaments become competent for contraction, the swiveling head of myosin pulls itself along the actin filament. This movement changes the shape of the pocket to which ADP is bound, freeing the ADP molecule.
R-HSA-445797 (Reactome) Once calcium influx occurs, calmodulin is activated by the binding of calcium. The active calmodulin complex binds and activates the smooth muscle myosin light chain kinase (Hathaway and Adelstein 1979, Webb 2003).
R-HSA-445813 (Reactome) The smooth muscle light chain kinase phosphorylates the smooth muscle light chains. This phosphorylation activates the myosin lights chains, effectively allowing contraction to begin.
R-HSA-5263628 (Reactome) Mechanical stress and repetitive muscle contraction often causes membrane disruption to the sarcolemma. Healthy muscle is able to repair these disruptions by a Ca2+-dependent pathway. The combination of dysferlin (DYSF), caveolin 3 (CAV3) and tripartite motif-containing protein 72 (TRIM72 aka MG53) appears to be essential for the repair of muscle membrane damage (Cai et al. 2009). DYSF subsequently binds annexin A6 (ANXA6), a member of a family of phospholipid-binding proteins in a Ca2+-dependent manner. This interaction has been demonstrated in imaging experiments in zebrafish (Roostalu U & Strahle 2012). This interaction creates a platform for interacting proteins at the sarcolemma membrane surface and sequential recruitment of annexin A1 and A2 (ANXA1 and 2) to the repair site. The human event is deduced on the basis of experiments performed in mice (Lennon et al. 2003).
R-HSA-5263633 (Reactome) Mechanical stress and repetitive muscle contraction often causes membrane disruption to the sarcolemma. Healthy muscle is able to repair these disruptions by a Ca2+-dependent pathway. The combination of dysferlin (DYSF), caveolin 3 (CAV3) and tripartite motif-containing protein 72 TRIM72 aka MG53) appears to be essential for the repair of muscle membrane damage (Cai et al. 2009). CAV3 probably acts as a scaffolding protein in caveolar membranes and can interact with DYSF (Matsuda et al. 2001), a surface membrane protein which promotes the fusion of intracellular vesicles with each other and with the sarcolemma at the site of injury. TRIM72 is required for transport of DYSF to the site of injury.
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
Smooth Muscle Myosin Light ChainR-HSA-445813 (Reactome)
TRIM72R-HSA-5263633 (Reactome)
p-S,T-PAK1,2TBarR-HSA-445797 (Reactome)
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