α2δ-2 is required for depolarization-induced suppression of excitation in purkinje cells

Kathleen A. Beeson, Gary L. Westbrook, Eric Schnell

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: α2δ proteins (CACNA2D1–4) are required for normal neurological function and contribute to membrane trafficking of voltage-gated calcium channels, through which calcium entry initiates numerous physiological processes. However, it remains unclear how α2δ proteins influence calcium-mediated signalling to control neuronal output. Using whole-cell recordings of mouse Purkinje cells, we show that α2δ-2 is required for functional coupling of postsynaptic voltage-dependent calcium entry with calcium-dependent effector mechanisms controlling two different outputs, depolarization-induced suppression of excitation and spike afterhyperpolarization. Our findings indicate an important role for α2δ-2 proteins in regulating functional postsynaptic calcium channel coupling in neurons, providing new context for understanding the effects of α2δ mutations on neuronal circuit function and presenting additional potential avenues to manipulate α2δ-mediated signalling for therapeutic gain. Key points: Calcium influx, via voltage-dependent calcium channels, drives numerous neuronal signalling processes with precision achieved in part by tight coupling between calcium entry and calcium-dependent effectors. α2δ proteins are important for neurological function and contribute to calcium channel membrane trafficking, although how α2δ proteins influence postsynaptic calcium-dependent signalling is largely unexplored. Here it is shown that loss of α2δ-2 proteins disrupts functional calcium coupling to two different postsynaptic calcium-dependent signals in mouse Purkinje cell neurons, retrograde endocannabinoid signalling and the action potential afterhyperpolarization. The findings provide new insights into the control of calcium coupling as well as new roles for α2δ-2 proteins in neurons.

Original languageEnglish (US)
JournalJournal of Physiology
DOIs
StateAccepted/In press - 2021

Keywords

  • calcium channels
  • depolarization-induced suppression of excitation
  • endocannabinoid signalling
  • nanodomains
  • purkinje cells
  • α2δ-2 proteins

ASJC Scopus subject areas

  • Physiology

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