Figure 2. Integrin positioning, complex formation, signaling and mechanotransduction in the myocyte.

A) Integrins contact ECM, transverse the sarcolemmal membrane at the costamere where they can interdigitates to the sarcomere as they connect to Z-line structures. Thus they bridge the ECM to sarcomere across the myocyte membrane and may even transmit information to the nucleus. Integrins are also located in the intercalated disc of the CM.

B) Enlarged portion from Panel A showing that integrin α7β1D, a predominant laminin receptor in the mature cardiac myocyte, can bridge the ECM to the sarcomere across the costamere where the integrin forms a complex of structural and signaling proteins.

C) Some important structural connectors which bind to the tails of the integrin receptor in the cardiac myocyte. Integrins connect and aggregate a range of adapter and signaling proteins such as integrin linked kinase (ILK), focal adhesion kinase (FAK), paxillin (Pax), vinculin (Vcl), talin (Tln), Kindlin, PINCH, Parvin, actinin and even actin. This allows both bridging of ECM to the cytoskeleton and perhaps sarcomere, and also allows propagation of signals bidirectionally across the cell membrane. Complex formation between ECM and integrins allows signals from the ECM to be directed into the cell, termed “outside-in” signaling”. Assembly of proteins on the integrin cytoplasmic domain tails can also occur as a result of signals produced from receptors distinct from integrins. With this, the assembled complex can “activate” integrins, change their conformation and allow enhanced interactions of integrins with ECM ligands, a process termed “inside-out” signaling. See text for details.

D) Illustration of some integrin signaling pathways in the cardiac myocyte. When integrins bind ECM ligands (e.g. laminin as illustrated here) they assemble proteins on their intracellular cytoplasmic domains and ultimately orchestrate signals down a variety of pathways such as those produced through Akt, JNK, ERK, p38 or NFκB. In turn, cellular events such as myocyte growth, hypertrophy or cell survival or death can occur. Of note is that mechanical events occuring outside the cardiac myocyte can stimulate the ECM-integrin interaction and also lead to intracellular biochemical changes, a process termed “mechanotransduction.” See text for details.

(ILK=integrin linked kinase; Mito=mitochondria; Pax=paxillin; Tln=talin; Vcl/MtVcl=vinculin and metavinculin, respectively; FAK=focal adhesion kinase)