Completed Brain & Nervous System Heart, Stroke & Blood

Physiological and pathological regulation of calcium channel trafficking and function

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £1.4M
Period Aug 2018 — Aug 2022

In plain English

AI plain-English summary

A genetically engineered mouse with a fluorescent tag on a key pain-signalling protein will reveal how nerve injury rewires calcium channels to cause chronic pain. Nerve damage can trigger neuropathic pain—a persistent, often debilitating condition that affects millions of people. Current treatments, including gabapentinoid drugs, work by targeting a protein called alpha2delta-1, but exactly how this protein controls calcium channels in pain-sensing neurons remains unclear. This project uses a new mouse model to track the N-type calcium channel (CaV2.2) in living tissue, and to cross it with mice lacking alpha2delta-1. The researchers will map where the channel sits in sensory neurons and spinal cord, how its location changes after nerve injury, and how alpha2delta-1’s maturation by a specific protease enables the channel to function. If successful, this fundamental science will identify the protease that processes alpha2delta-1 as a potential new drug target for chronic pain. That could lead to treatments with fewer side effects than current gabapentinoids, which act broadly. The work also clarifies a basic mechanism of neurotransmitter release—knowledge that, historically, has underpinned advances in neurology and anaesthesia.

View original technical description
Voltage-gated CaV2 calcium-channels are essential for presynaptic neurotransmitter release. Knowledge of factors governing the regulation in neurons of N-type (CaV2.2) calcium-channel trafficking and properties is key to understanding their pathological role in neuropathic pain. Both CaV2.2 and the auxiliary subunit alpha2delta-1, which is up-regulated in neuropathic pain models, represent validated pain therapeutic targets. My overarching research aim is to address fundamental questions regarding N-type calcium-channel trafficking and function. For this, we will exploit our key development of a knock-in mouse containing HA-tagged CaV2.2. Firstly, we will analyse expression of CaV2.2 in sensory neurons and spinal cord, and its dysregulation following neuropathic insult. We will examine the role of alpha2delta-1 by making double transgenics with alpha2delta-1 knock-out mice. Secondly, we will dissect the interdependent dual roles of alpha2delta subunits in permitting voltage-dependent activation of CaV2.2 channels and promoting their trafficking, concentrating on the essential requirement for proteolytic maturation of alpha2delta. Finally, we will address the identity and subcellular localisation of the protease involved in alpha2delta processing, since it represents a potential novel therapeutic target in chronic pain. This study will parse out the multiple roles of alpha2delta-subunits in N-type calcium-channel function, and elucidate the molecular mechanism of the alpha2delta-ligand gabapentinoid drugs.

View the original record at the funder ↗

Researchers

Annette Dolphin (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The role of alpha2delta subunits in calcium channel function under physiological and pathological conditions
Role of voltage-dependent calcium channels in nociceptive transmission under normal and neuropathic conditions
HCN ion channels and pain
Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins.
Role of HCN ion channels in pain

Original classification

Investigator Award in Science

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