HERG K+ channels activation during beta(1) integrin-mediated adhesion to fibronectin induces an up-regulation of alpha(v)beta(3) integrin in the preosteoclastic leukemia cell line FLG 29.1

Integrin receptors have been demonstrated to mediate either "inside-to-out" and "outside-to-in" signals, and by this way are capable of regulating man y cellular functions, such as cell growth and differentiation, cell migrati on, and activation. Among the various integrin-centered signaling pathways discovered so far, we demonstrated that the modulation of the electrical po tential of the plasma membrane (V-REST) is an early integrin-mediated signa l, which is related to neurite emission in neuroblastoma cells. This modula tion is sustained by the activation of HERG K+ channels, encoded by the eth er-a-go-go-related gene (herg). The involvement of integrin-mediated signal ing is being discovered in the hemopoietic system: in particular, osteoclas ts are generated as well as induced to differentiate by interaction of oste oclast progenitors with the stromal cells, through the involvement of integ rin receptors. We studied the effects of cell interaction with the extracel lular matrix protein fibronectin (FN) in a human leukemic preosteoclastic c ell line (FLG 29.1 cells), which has been demonstrated to express HERG curr ents. We report here that FLG 29.1 cells indeed adhere to purified FN throu gh integrin receptors, and that this adhesion induces an osteoclast phenoty pe in these cells, as evidenced by the appearance of tartrate-resistant aci d phosphatase, as well as by the increased expression of CD51/alpha (v)beta (3) integrin and calcitonin receptor. An early activation of HERG current (I-HERG), without any increase in herg RNA or modifications of HERG protein was also observed in FN-adhering cells. This activation is apparently sust ained by the beta (1), integrin subunit activation, through the involvement of a pertussis-toxin sensitive G(i) protein, and appears to be a determina nt signal for the up-regulation of alpha (v)beta (3) integrin, as well as f or the increased expression of calcitonin receptor.