Bimodal control of a Ca2+-activated Cl- channel by different Ca2+ signals

Ca2+-activated Cl- channels play important roles in a variety of physiological processes, including epithelial secretion, maintenance of smooth muscle tone, and repolarization of the cardiac action potential. It remains unclear; however, exactly how these channels are controlled by Ca2+ and voltage. Excised inside-out patches containing many Ca2+-activated Cl- channels from Xenopus oocytes were used to study channel regulation The currents were mediated by a single type of Cl- channel that exhibited an anionic selectivity of I- > Br- > Cl- (3.6:1.9:1.0), irrespective of the direction of the current flow or [Ca2+]. However, depending on the amplitude of the Ca2+ signal, this channel exhibited qualitatively different behaviors. At [Ca2+] < 1 mu M, the currents activated slowly upon depolarization and deactivated upon hyperpolarization and the steady state cur-rent-voltage relationship was strongly outwardly rectifying. At higher [Ca2+], the currents did not rectify and were time independent. This difference in behavior at different [Ca2+] was explained by an apparent voltage-dependent Ca2+ sensitivity of the channel. Ar +120 mV the EC50 for channel activation by Ca2+ was approximately fourfold less than at -120 mV (0.9 vs. 4 mu M) Thus, at [Ca2+] < 1 mu M, inward current was smaller than outward current and the currents were time dependent as a consequence of voltage-dependent changes in Ca2+ binding. The voltage-dependent Ca2+ sensitivity was explained by a kinetic gating scheme in which channel activation was Ca2+ dependent and channel closing was voltage sensitive. This scheme was supported by the observation that deactivation time constants of currents produced by rapid Ca2+ concentration jumps were voltage sensitive, but that the activation-time constants were Ca2+ sensitive. The deactivation time constants increased linearly with the log of membrane potential. The qualitatively different behaviors of this channel in response to different Ca2+ concentrations adds a new dimension to Ca2+ signaling: the same channel can mediate either excitatory or inhibitory responses, depending on the amplitude of the cellular Ca2+ signal.