Biphasic, Opposing Modulation of Cloned Neuronal α1E Ca Channels by Distinct Signaling Pathways Coupled to M2 Muscarinic Acetylcholine Receptors – ScienceOpen
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      Biphasic, Opposing Modulation of Cloned Neuronal α1E Ca Channels by Distinct Signaling Pathways Coupled to M2 Muscarinic Acetylcholine Receptors

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          Abstract

          Neuronal α1E 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 α1E exhibit striking biphasic modulation. Receptor activation first produces rapid inhibition of current amplitude and activation rate. However, in the continued presence of agonist, α1E 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 α1E 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 β2a or β3 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 α1E, Ca channels formed by α1A or α1B display only inhibition and no stimulation during prolonged activation of M2 receptors. The dual modulation of α1E 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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          15 August 1999
          : 19
          : 16
          : 6806-6817
          Affiliations
          [ 1 ]Department of Physiology and Biophysics, University of Iowa, College of Medicine, Iowa City, Iowa 52242-1109
          Article
          PMC6782876 PMC6782876 6782876 3313
          10.1523/JNEUROSCI.19-16-06806.1999
          6782876
          10436038
          1d0b3af3-06cf-4f34-86a7-664a0105af70
          Copyright © 1999 Society for Neuroscience
          History
          : 1 March 1999
          : 26 May 1999
          : 28 May 1999
          Categories
          Article
          Custom metadata
          5.00

          G-protein,neuronal integration,phosphorylation,presynaptic inhibition,electrophysiology,neurosecretion,patch-clamp recording,protein kinases,HEK293 cells,α1A,α1B,R-type Ca channel,ion channel modulation

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