Elegant computer modeling supports the role of tension in stabilizing attachments

found as monomer in the prostate and in human pigment cells in a monomeric and dimeric form. Activation of OR51E1 in cardiomyocytes We observed that stimulation of cardiomyocytes with OR51E1 agonist leads to inhibition of the spontaneous Ca2 transients. We showed that this negative chronotropic effect is dose-dependent over the micromolar-to-millimolar range. Detailed analysis revealed that regardless of which type of stem cell-derived cardiomyocytes was investigated, the nonanoic acid-induced effect remained unchanged. We tested whether other mediumchain fatty acids also reduce the frequency of Ca2 spikes and found that the OR51E1 agonists decanoic, dodecanoic and tetradecanoic acid elicited similar effects, whereas compounds that were inactive on the heterologously expressed OR51E1 did not affect the Ca2 spike frequency. We next aimed to investigate the OR51E1-induced DHMEQ manufacturer signaling cascade. In olfactory receptor neurons, activation of an olfactory receptor leads to an activation of adenylyl Discussion Expression of OR51E1 in the human heart A variety of ORs are expressed in diverse non-olfactory human tissues, including the brain, the lung, the kidney and the prostate. However, the functional role of these ORs has only been investigated in a few tissues. OR51E1 was primarily identified in the prostate and is overexpressed in prostate cancer. Moreover, the inhibitory G protein could also be a putative interaction partner of OR51E1 due to the finding that Gai protein was weakly co-precipitated with OR51E1 protein. Recently, it was shown that beside Gaolf also Gao is functionally coupled to ORs in olfactory sensory neurons. 123 Basic Res Cardiol 112:13 Page 15 of 20 13 Furthermore, we could observe the involvement of the bc subunit of the G protein in the nonanoic PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19794329 acid-induced effect. The G protein bc subunits interact with effector molecules, such as phospholipases, adenylyl cyclase and ion channels, in a manner that leads to their activation or inhibition. Therefore, it is not surprising that the bc subunit is discussed as a drug target, inter alia, for preventing heart failure. OR signaling via bc subunits was previously described in olfactory sensory neurons and was also demonstrated for ectopically expressed OR51E2, a paralog of OR51E1, in prostate cancer cells. Classical cardiac GPCRs such as the muscarinic acetylcholine receptor M2 and adrenergic receptors also act via the bc subunit in the heart. Interestingly, bitter taste receptor agonists elicit G protein bc-dependent negative inotropy in the murine heart. Thus, we suggest that OR51E1 activation leads to GIRK channel opening via Gbc subunit. This opening leads to a hyperpolarization of the cell, which counteracts the HCN channel-induced depolarization, resulting in a reduction of the Ca2 spike frequency. However, we could not deduce whether the interaction between G protein bc subunits and other effector molecules primarily mediates the negative chronotropic effect or if the Gbc subunit only enhances the effect without playing a key role. We also found that OR51E1 agonists evoked negative inotropic effects on explanted heart preparations. The reduction of contractility of adult human myocardium stimulated with MCFA was dose-dependent and occurred over a similar dose range as the negative chronotropic effect in stem cell-derived cardiomyocytes, possibly indicating the involvement of a similar G protein bc-mediated signal transduction. It is well recognized that bc subunits contribu