The vitamin D receptor agonist elocalcitol upregulates L-type calcium channel activity in human and rat bladder

Morelli, Annamaria; Squecco, Roberta; Failli, Paola; Filippi, Sandra; Vignozzi, Linda; Chavalmane, A. K.; Fibbi, B.; Mancina, R.; Luciani, G.; Gacci, M.; Colli, E.; Francini, Fabio; Adorini, L.; Maggi, Mario

doi:10.1152/ajpcell.90634.2007

Human bladder contraction mainly depends on Ca2+ influx via L-type voltage-gated Ca2+ channels and on RhoA/Rho kinase contractile signaling, which is upregulated in overactive bladder (OAB). Elocalcitol is a vitamin D receptor agonist inhibiting RhoA/Rho kinase signaling in rat and human bladder. Since in the normal bladder from Sprague-Dawley rats elocalcitol treatment delayed the carbachol-induced contraction without changing maximal responsiveness and increased sensitivity to the L-type Ca2+ channel antagonist isradipine, we investigated whether elocalcitol upregulated L-type Ca2+ channels in human bladder smooth muscle cells (hBCs). In hBCs, elocalcitol induced a rapid increase in intracellular [Ca2+], which was abrogated by the L-type Ca2+ channel antagonist verapamil. Moreover, hBCs exhibited L-type voltage-activated Ca2+ currents (I Ca), which were selectively blocked by isradipine and verapamil and enhanced by the selective L-type agonist BAY K 8644. Addition of elocalcitol (10(-7) M) increased L-type I Ca size and specific conductance by inducing faster activation and inactivation kinetics than control and BAY K 8644, while determining a significant negative shift of the activation and inactivation curves, comparable to BAY K 8644. These effects were strengthened in long-term treated hBCs with elocalcitol (10(-8) M, 48 h), which also showed increased mRNA and protein expression of pore-forming L-type alpha(1C)-subunit. In the bladder from Sprague-Dawley rats, BAY K 8644 induced a dose-dependent increase in tension, which was significantly enhanced by elocalcitol treatment (30 microg.kg(-1).day(-1), 2 wk). In conclusion, elocalcitol upregulated Ca2+ entry through L-type Ca2+ channels in hBCs, thus balancing its inhibitory effect on RhoA/Rho kinase signaling and suggesting its possible efficacy for the modulation of bladder contractile mechanisms.

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Titolo:	The vitamin D receptor agonist elocalcitol upregulates L-type calcium channel activity in human and rat bladder
Autori di Ateneo:	MORELLI, ANNAMARIA SQUECCO, ROBERTA FAILLI, PAOLA FILIPPI, SANDRA VIGNOZZI, LINDA A.K. Chavalmane B. Fibbi R. Mancina G. Luciani M. Gacci E. Colli FRANCINI, FABIO L. Adorini MAGGI, MARIO mostra contributor esterni nascondi contributor esterni
Autori:	MORELLI, ANNAMARIA; SQUECCO, ROBERTA; FAILLI, PAOLA; FILIPPI, SANDRA; VIGNOZZI, LINDA; A.K. Chavalmane; B. Fibbi; R. Mancina; G. Luciani; M. Gacci; E. Colli; FRANCINI, FABIO; L. Adorini; MAGGI, MARIO
Data di pubblicazione:	2008
Rivista:	AMERICAN JOURNAL OF PHYSIOLOGY. CELL PHYSIOLOGY
Volume:	294
Pagina iniziale:	C1206
Pagina finale:	C1214
Abstract:	Human bladder contraction mainly depends on Ca2+ influx via L-type voltage-gated Ca2+ channels and on RhoA/Rho kinase contractile signaling, which is upregulated in overactive bladder (OAB). Elocalcitol is a vitamin D receptor agonist inhibiting RhoA/Rho kinase signaling in rat and human bladder. Since in the normal bladder from Sprague-Dawley rats elocalcitol treatment delayed the carbachol-induced contraction without changing maximal responsiveness and increased sensitivity to the L-type Ca2+ channel antagonist isradipine, we investigated whether elocalcitol upregulated L-type Ca2+ channels in human bladder smooth muscle cells (hBCs). In hBCs, elocalcitol induced a rapid increase in intracellular [Ca2+], which was abrogated by the L-type Ca2+ channel antagonist verapamil. Moreover, hBCs exhibited L-type voltage-activated Ca2+ currents (I Ca), which were selectively blocked by isradipine and verapamil and enhanced by the selective L-type agonist BAY K 8644. Addition of elocalcitol (10(-7) M) increased L-type I Ca size and specific conductance by inducing faster activation and inactivation kinetics than control and BAY K 8644, while determining a significant negative shift of the activation and inactivation curves, comparable to BAY K 8644. These effects were strengthened in long-term treated hBCs with elocalcitol (10(-8) M, 48 h), which also showed increased mRNA and protein expression of pore-forming L-type alpha(1C)-subunit. In the bladder from Sprague-Dawley rats, BAY K 8644 induced a dose-dependent increase in tension, which was significantly enhanced by elocalcitol treatment (30 microg.kg(-1).day(-1), 2 wk). In conclusion, elocalcitol upregulated Ca2+ entry through L-type Ca2+ channels in hBCs, thus balancing its inhibitory effect on RhoA/Rho kinase signaling and suggesting its possible efficacy for the modulation of bladder contractile mechanisms.
Handle:	http://hdl.handle.net/2158/339346
Appare nelle tipologie:	1a - Articolo su rivista

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