Abstract
Neuronal high-voltage-activated (HVA) Ca2+ channels are rapidly inactivated by a mechanism that is termed Ca2+-dependent inactivation (CDI). In this study we have shown that β-adrenergic receptor (βAR) stimulation inhibits CDI in rat thalamocortical (TC) relay neurons. This effect can be blocked by inhibition of cAMP-dependent protein kinase (PKA) with a cell-permeable inhibitor (myristoylated protein kinase inhibitor-(14–22)-amide) or A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide, suggesting a critical role of these molecules downstream of the receptor. Moreover, inhibition of protein phosphatases (PP) with okadaic acid revealed the involvement of phosphorylation events in modulation of CDI after βAR stimulation. Double fluorescence immunocytochemistry and pull down experiments further support the idea that modulation of CDI in TC neurons via βAR stimulation requires a protein complex consisting of CaV1.2, PKA and proteins from the AKAP family. All together our data suggest that AKAPs mediate targeting of PKA to L-type Ca2+ channels allowing their phosphorylation and thereby modulation of CDI.
Highlights
Voltage-gated Ca2+ channels of the plasma membrane consist three subfamilies (CaV1, CaV2 and CaV3) [1]
In a first attempt to investigate the modulation of Ca2+dependent inactivation (CDI) via b-adrenergic receptor (bAR), we analyzed the expression patterns of the main components of the proposed b-AR signaling pathway in dorsal part of the lateral geniculate nucleus (dLGN) TC neurons by performing Reverse transcription-polymerase chain reaction (RT-PCR) analyses on a tissue and single cell level
Dissociated cells were observed under an inverted microscope and small bipolar interneurons and larger multipolar TC neurons were visually identified by using established criteria [22,23]
Summary
Voltage-gated Ca2+ channels of the plasma membrane consist three subfamilies (CaV1, CaV2 and CaV3) [1]. They are composed of 10 pore-forming a1 channel subunits and are important components of a universal cellular Ca2+ signaling tool kit [2]. Voltage-dependent Ca2+ channels are one of the main routes of cellular Ca2+ entry. Intracellular Ca2+ ions control processes as diverse as cell proliferation, neuronal development and transmitter release [2]. All of these functions have to be accomplished within a narrow range of Ca2+ concentrations. We have shown that in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN), Ca2+-induced Ca2+ release (CICR) contributes to intracellular Ca2+ transients [5], leads to the activation of Ca2+-dependent K+
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