Homer 1a enhances spike‐induced calcium influx via L‐type calcium channels in neocortex pyramidal cells

Abstract

The scaffold protein family Homer/Vesl serves to couple surface receptors or channels with endoplasmic calcium release channels. Homer 1a/Vesl-1S is regarded as regulating such coupling in an activity-dependent manner. The present calcium photometry and electrophysiological measurement revealed that Homer 1a up-regulates voltage-dependent calcium channels (VDCCs), depending on inositol-1,4,5-trisphosphate (IP3) receptors (IP3Rs). In rat neocortex pyramidal cells, intracellular injection by diffusion from the patch pipette (referred to as 'infusion') of Homer 1a protein enhanced spike-induced calcium increase, depending on both the protein concentration and spike frequency. Induction of this enhancement was disrupted by blockers of key molecules of the mGluR-IP3 signalling pathway, including metabotropic glutamate receptors (mGluRs), phospholipase C and IP3Rs. However, infusion of IP3 failed to mimic the effect of Homer 1a, suggesting requirement for a second Homer 1a-mediated signalling as well as the mGluR-IP3 signalling. In contrast to the induction, maintenance of this enhancement was independent of the mGluR-IP3 signalling, taking the form of augmented calcium influx via L-type VDCCs. Presumably due to the VDCC up-regulation, threshold currents for calcium spikes were reduced. Given that Homer 1a induction is thought to down-regulate neural excitability and hence somatic spike firing, this facilitation of calcium spikes concomitant with such attenuated firing may well have a critical impact on bi-directional synaptic plasticity.

Homer proteins in Ca2+ signaling by excitable and non-excitable cells

“…On the other hand, Homer1 directly interacts with the α1C subunit of Ca v 1.2 and activates Ca v 1.2 channel function. However, unlike the finding in neurons [23], both H1a and H1b activated the expressed Ca v 1.2 and the native Ca v 1.2 in detrusor muscle cells [25]. [25].…”

“…In addition to the mGluRs, many Ca 2+ signaling proteins express Homer ligands and bind Homer. Among them are the scaffolding protein Shank [8], PLCβ [16,17], IP 3 receptors (IP 3 Rs) [15,18], TRPC channels [15,18], ryanodine receptors (RyRs) [19][20][21][22] and selective L-type Ca 2+ channel isoforms [23][24][25].…”

“…Indeed, measurement of Ca 2+ release in permeabilized skeletal muscle fibers and the activity of RyRs reconstituted into lipid bilayers show that Homer1 activates the skeletal and cardiac muscle RyR isoforms RyR1 [19][20][21] and RyR2 [22]. In addition, infusion and expression of H1a, but not H1b, activates the L-type Ca 2+ current in neocortex pyramidal neurons [23]. However, whether Homer1 similarly affects the channels in vivo and how these potential effects of Homer1 are translated to a role of Homer1 in E-C coupling has been resolved only recently [25].…”

The Homer-1 protein Ania-3 interacts with the plasma membrane calcium pump

“…Intriguingly, the PMCA was detected by confocal immunofluorescence microscopy as part of this network [40]. The rapidly inducible expression of short "dominant-negative" forms of Homer (such as Ania-3 and Homer 1a) modulates synaptic signaling by altering metabotropic glutamate receptor trafficking and dissociating functional protein-protein interactions within the signaling complex [11,17,18,20,27]. Similarly, the different Homer splice variants may influence the amplitude and duration of local Ca 2+ signals by reversibly recruiting the PMCAs into these signaling domains.…”

“…These forms lack the C-terminal dimerization region and competitively interfere with the normal linkage between Homer-binding proteins. Indeed, expression of Homer 1a has physiological effects that include disruption of mGluR5-Homer 1b/1c-IP3 complexes [9], alteration of mGluR-induced Ca 2+ release [10], and extracellular calcium influx [20].…”