beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.

Voltage-dependent calcium channels (VDCCs) play a pivotal role in normal excitation-contraction coupling in cardiac myocytes. These channels can be modulated through activation of beta-adrenergic receptors (beta-ARs), which leads to an increase in calcium current (I(Ca-L)) density through cardiac Ca(v)1 channels as a result of phosphorylation by cAMP-dependent protein kinase A. Changes in I(Ca-L) density and kinetics in heart failure often occur in the absence of changes in Ca(v)1 channel expression, arguing for the importance of post-translational modification of these channels in heart disease.

Teaching resources. Using web-based discussion forums as a model of the peer-review process and a tool for assessment.

This Teaching Resource describes how to use an online asynchronous discussion as a mechanism to introduce students to the peer-review process, as well as to assess student performance and understanding. This method was applied to a graduate course on signal transduction and the Teaching Resource includes a syllabus, detailed plan for incorporating the online discussion, sample journal club questions, and sample student responses to the discussion forum, faculty responses, and student revisions.

Inquiry learning. Integrating content detail and critical reasoning by peer review.

Classroom lectures by experts in combination with journal clubs and Web-based discussion forums help graduate students develop critical reasoning skills.

Arrestin is required for agonist-induced trafficking of voltage-dependent calcium channels.

Many metabotropic receptors in the nervous system act through signaling pathways that result in the inhibition of voltage-dependent calcium channels. Our previous findings showed that activation of seven-transmembrane receptors results in the internalization of calcium channels. This internalization takes place within a few seconds, raising the question of whether the endocytic machinery is in close proximity to the calcium channel to cause such rapid internalization.

G protein-induced trafficking of voltage-dependent calcium channels.

Calcium channels are well known targets for inhibition by G protein-coupled receptors, and multiple forms of inhibition have been described. Here we report a novel mechanism for G protein-mediated modulation of neuronal voltage-dependent calcium channels that involves the destabilization and subsequent removal of calcium channels from the plasma membrane. Imaging experiments in living sensory neurons show that, within seconds of receptor activation, calcium channels are cleared from the membrane and sequestered in clathrin-coated vesicles.

Mapping of RGS12-Cav2.2 channel interaction.

The alpha1 (pore-forming) subunit of the Cav2.2 (N-type) channel is tyrosine phosphorylated by Src kinase upon activation of GABAB receptors. The tyrosine-phosphorylated form of the alpha1 subunit of the Cav2.

Ca2+ channels as integrators of G protein-mediated signaling in neurons.

The observations from Dunlap and Fischbach that transmitter-mediated shortening of the duration of action potentials could be caused by a decrease in calcium conductance led to numerous studies of the mechanisms of modulation of voltage-dependent calcium channels. Calcium channels are well known targets for inhibition by receptor-G protein pathways, and multiple forms of inhibition have been described. Inhibition of Ca(2+) channels can be mediated by G protein betagamma-subunits or by kinases, such as protein kinase C and tyrosine kinases.

N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects.

An emerging concept in signal transduction is the organization of neuronal receptors and channels into microdomains in which signaling proteins are brought together to regulate functional responses. With the multiplicity of potential protein-protein interactions arises the need for the regulation and timing of these interactions. We have identified N-type Ca(2+) channel-signaling molecule complexes formed at different times upon activation of gamma-aminobutyric acid, type B, receptors.