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The Journal of Neuroscience, August 15, 1999, 19(16):6806-6817

Biphasic, Opposing Modulation of Cloned Neuronal 1E Ca Channels by Distinct Signaling Pathways Coupled to M2 Muscarinic Acetylcholine Receptors

Ulises Meza, Roger Bannister, Karim Melliti, and Brett Adams

Department of Physiology and Biophysics, University of Iowa, College of Medicine, Iowa City, Iowa 52242-1109

Neuronal 1E subunits are thought to form R-type Ca channels. When expressed in human embryonic kidney cells with M2 muscarinic acetylcholine receptors, Ca channels encoded by rabbit 1E exhibit striking biphasic modulation. Receptor activation first produces rapid inhibition of current amplitude and activation rate. However, in the continued presence of agonist, 1E currents subsequently increase. Kinetic slowing persists during this secondary stimulation phase. After receptor deactivation, kinetic slowing is quickly relieved, and current amplitude over-recovers before returning toward control levels. These features indicate that inhibition and stimulation of 1E are separate processes, with stimulation superimposed on inhibition. Pertussis toxin eliminates inhibition without affecting stimulation, demonstrating that inhibition and stimulation involve distinct signaling pathways. Neither inhibition nor stimulation is altered by coexpression of Ca channel 2a or 3 subunits. Stimulation is abolished by staurosporine and reduced by intracellular 5'-adenylylimidodiphosphate, suggesting that phosphorylation is required. However, stimulation does not seem to involve cAMP-dependent protein kinase, protein kinase C, cGMP-dependent protein kinase, tyrosine kinases, or phosphoinositide 3-kinases. Stimulation does not require a Ca signal, because it is not specifically altered by varying intracellular Ca buffering or by substituting Ba as the charge carrier. In contrast to those formed by 1E, Ca channels formed by 1A or 1B display only inhibition and no stimulation during prolonged activation of M2 receptors. The dual modulation of 1E may confer unique physiological properties on native R-type Ca channels. As one possibility, R-type channels may continue to mediate Ca influx during steady inhibition of N-type and P/Q-type channels by muscarinic or other receptors.

Key words: 1A; 1B; R-type Ca channel; G-protein; ion channel modulation; neurosecretion; presynaptic inhibition; neuronal integration; HEK293 cells; electrophysiology; patch-clamp recording; phosphorylation; protein kinases

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19166806-12$05.00/0

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