Membrane depolarization and intracellular calcium transients generated by activation of voltage-gated sodium and calcium channels are local signals, which initiate physiological processes such as action potential conduction, synaptic transmission, and excitation-contraction coupling. Targeting of effector proteins and regulatory proteins to ion channels is an important mechanism to ensure speed, specificity, and precise regulation of signaling events in response to local stimuli. In this article, we review recent experimental results showing that sodium and calcium channels form local signaling complexes, in which effector proteins, anchoring proteins, and regulatory proteins interact directly with ion channels. The intracellular domains of these channels serve as signaling platforms, mediating their participation in intracellular signaling processes. These protein-protein interactions are important for efficient synaptic transmission and for regulation of ion channels by neurotransmitters and intracellular second messengers. These localized signaling complexes are essential for normal function and regulation of electrical excitability, synaptic transmission, and excitation-contraction coupling.
In hippocampal pyramidal cells, dopamine acts at D1 receptors to reduce peak Na ؉ currents by activation of phosphorylation by PKA anchored via an A kinase-anchoring protein (AKAP15). However, the mechanism by which AKAP15 anchors PKA to neuronal Na ؉ channels is not known. By using a strategy of coimmunoprecipitation from transfected tsA-201 cells, we have found that AKAP15 directly interacts with Na v1.2a channels via the intracellular loop between domains I and II. This loop contains key functional phosphorylation sites. Mutagenesis indicated that this interaction occurs through a modified leucine zipper motif near the N terminus of the loop. Whole-cell patch clamp recordings of acutely dissociated hippocampal pyramidal cells revealed that the D1 dopamine receptor agonist SKF 81297 reduces peak Na ؉ current amplitude by 20.5%, as reported previously. Disruption of the leucine zipper interaction between Na v1.2a and AKAP15 through the inclusion of a small competing peptide in the patch pipette inhibited the SKF 81297-induced reduction in peak Na ؉ current, whereas a control peptide with mutations in amino acids important for the leucine zipper interaction did not. Our results define the molecular mechanism by which G protein-coupled signaling pathways can rapidly and efficiently modulate neuronal excitability through local protein phosphorylation of Na ؉ channels by specifically anchored PKA. sodium channel V oltage-dependent Na ϩ channels play a primary role in neuronal excitability (1) and are a critical target for neuromodulation (2). The Na ϩ channel ␣ subunit is phosphorylated by PKA in vitro (3, 4) and in intact cells (5), and this reduces peak Na ϩ current in expression systems (6-9) and in neurons (6,8). Recent research has established that neuromodulation of the Na ϩ channel by PKA, as well as PKC, is caused by voltagedependent enhancement of intrinsic slow inactivation (10, 11).The hippocampus receives rich dopaminergic innervation from the mesocorfico limbic system (12). Activation of D1-like dopamine receptors, which stimulates adenylate cyclase activity (13), reduces peak Na ϩ current amplitude in hippocampal pyramidal cells without altering the voltage dependence of activation or fast inactivation (8). This effect is caused by PKA phosphorylation of a family of key sites in the intracellular loop connecting domains I and II of the channel (8,9,14). Na ϩ channels bind PKA via interaction with A kinase anchoring protein 15 (AKAP15) (15). Effective neuromodulation by PKA requires anchoring of the kinase to the channel by AKAP15 (16). AKAP15 interacts with L I-II of the neuronal Na ϩ channel (14), which is the region of the channel that contains most of the functionally significant phosphorylation sites (8,9,14,(17)(18)(19). However, the site and mechanism through which this interaction occurs are unknown.AKAPs are functionally related proteins having a targeting domain that directs them to a specific subcellular compartment or substrate and a kinase-anchoring domain with an amphipathic ␣-helix that ...
Electric fish communicate with electric organ (EO) discharges (EODs) that are sexually dimorphic, hormone-sensitive, and often individually distinct. The cells of the EO (electrocytes) of the weakly electric fish Sternopygus possess delayed rectifying K+ currents that systematically vary in their activation and deactivation kinetics, and this precise variation in K+ current kinetics helps shape sex and individual differences in the EOD. Because members of the Kv1 subfamily produce delayed rectifier currents, we cloned a number of genes in the Kv1 subfamily from the EO of Sternopygus. Using our sequences and those from genome databases, we found that in teleost fish Kv1.1 and Kv1.2 exist as duplicate pairs (Kv1.1a&b, Kv1.2a&b) whereas Kv1.3 does not. Using real-time quantitative RT-PCR, we found that Kv1.1a and Kv1.2a, but not Kv1.2b, expression in the EO is higher in high EOD frequency females (which have fast EO K+ currents) than in low EOD frequency males (which have slow EO K+ currents). Systemic treatment with dihydrotestosterone decreased Kv1.1a and Kv1.2a, but not Kv1.2b, expression in the EO, whereas treatment with human chorionic gonadotropin (hCG) increased Kv1.2a but not Kv1.1a or Kv1.2b expression in the EO. Thus, systematic variation in the ratios of Kv1 channels expressed in the EO is correlated with individual differences in and sexual dimorphism of a communication signal.
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