However, OAG is a fairly unspecific activator of TRPC channels, so effects cannot be attributed Vismodegib structure with confidence to TRPC3. 60 The vanilloid TRP channel 2 (TRPV2 (http://www.ncbi.nlm.nih.gov/gene/51393))

has been reported to be mechanosensitive (studied using cell-volume changes and patch pipette suction 61 ) and is expressed in the mouse heart. 44,62 Using the TRPV2 agonist probenicid in wild-type and TRPV2− / −  constitutive knockout mice, it was shown that this channel appears to contribute to baseline cardiac function, participating in the calcium-handling machinery of heart cells. 62 TRPV4 (http://www.ncbi.nlm.nih.gov/gene/59341) mRNA is weakly expressed in cardiac muscle, 63 and TRPV4 protein was located in cultured neonatal rat ventricular myocytes only in the nucleus. 64 However, caution is warranted here, regarding mRNA or protein expression in tissue. Firstly, mRNA and protein expression levels do not necessarily correlate 65 and secondly, while high expression levels are confirmatory of a significant presence

and indicative of functional relevance, low expression in whole tissue homogenates should be interpreted with care. If a protein is present in minority cell populations of the heart (such as Purkinje fibres), it could be of immense functional relevance, even if it was only detected at trace levels. In addition, some SAC, such as TREK, may be expressed at the membrane, but can be strongly inhibited in resting conditions,

66 making the assessment of availability of functional channels even more difficult. Finally, the melastatin TRP channel 4 (TRPM4) is expressed in cardiomyocytes, 45 and has been implicated in stretch-activated responses of vasculature smooth muscle cells. 67 Overexpression of TRPM4 may be involved in an inheritable form of progressive familial heart block type I, 68 and the identification of a possible stretch-activated component of this disease – mediated by TRPM4 – would be of pronounced clinical relevance. Thus, in addition to TRPC1 and TRPC6, the ion channels TRPC3, TRPV2, TRPV4 and TRPM4 form translationally-relevant targets for further basic and applied research. Piezo1 The discovery of Piezo1 and Piezo2 (http://www.ncbi.nlm.nih.gov/gene/63895) by Patapoutian’s GSK-3 group in 2010 46 represents one of the most important breakthroughs in the field of mechanotransduction in recent years. Piezo1 was initially identified in the neuro-2a neuronal cell line by siRNA knockdown of the expression of membrane proteins with unknown function. Knockdown of the FAM38A (http://www.ncbi.nlm.nih.gov/gene/415849) gene inhibited ISAC,NS and the gene product was named Piezo1. Mechanosensitivity was confirmed by heterologous expression of Piezo1 in HEK cells, which induced a robust ISAC,NS.