# Sodium and Calcium Channels: Structure, Function, Neuroplasticity, and Disease

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2021 · $1,111,616

## Abstract

Voltage-gated sodium (Nav) and calcium (Cav) channels generate action potentials and initiate synaptic
transmission in neurons. Mutations in them cause inherited epilepsy, migraine, chronic pain, and periodic
paralysis, and they are important molecular targets for drugs. A. New insights into structure and function of Nav
channels have come from our high-resolution x-ray crystallography of their bacterial ancestor NavAb. We will
further define the structural basis for key functional properties of mammalian Nav channels by building their
characteristic structural features into NavAb, including the structural basis for voltage-dependent activation, ion
selectivity, and fast inactivation. Based on these results, we will determine the structural basis for impaired Nav
channel function by mutations that cause periodic paralysis and the chronic pain syndromes erythromelalgia
and paroxysmal extreme pain disorder. B. Failure of learning and memory is a debilitating aspect of aging and
neurodegenerative disease, yet we do not understand the basic mechanisms of these crucial brain processes
and we cannot intervene effectively in these deficits. Learning and memory takes place primarily at synapses.
Presynaptic calcium (Cav2.1) channels initiate neurotransmitter release at most synapses in the brain. The
activity of these channels is tightly regulated by a large complex of signaling proteins, including calmodulin and
related calcium-sensor proteins. Our work implicates Cav2.1 channel regulation in short-term synaptic plasticity
in transfected synapses in cultured neurons and in a novel mouse model in which the IM-AA mutation is
inserted into Cav2.1. We will further define the molecular and structural mechanism for Cav2.1 channel
regulation, determine the role of regulation of Cav2.1 channels in short-term synaptic plasticity of neural
circuits, and explore the role of regulation of Cav2.1 channels and short-term synaptic plasticity in spatial
learning and memory. Our experiments with this unique mouse model will give unique insights into the
mechanism of short-term presynaptic plasticity in hippocampal neurons and its role in integrative bbrain
function. C. Dravet Syndrome (DS) is a devastating childhood neuropsychiatric disorder caused by de novo,
heterozygous loss-of-function mutations in Nav1.1. We developed a mouse genetic model with all the features
of DS, including thermally induced and spontaneous seizures, ataxia, circadian rhythm and sleep disorders,
cognitive deficit, autistic-like features, and premature death via SUDEP. Physiological and genetic studies
show that all these effects are correlated with loss of Na currents and excitability of GABAergic interneurons,
without consistent effects on excitatory neurons, which causes imbalance of excitation vs. inhibition in neural
circuits. To further advance understanding of pathophysiology and treatment of DS, we will determine the
neural cells and circuits responsible for DS using specific deletion by...

## Key facts

- **NIH application ID:** 10136735
- **Project number:** 5R35NS111573-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** WILLIAM A CATTERALL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,111,616
- **Award type:** 5
- **Project period:** 2019-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136735

## Citation

> US National Institutes of Health, RePORTER application 10136735, Sodium and Calcium Channels: Structure, Function, Neuroplasticity, and Disease (5R35NS111573-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136735. Licensed CC0.

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