Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation

Area of Science:

• Molecular biology
• Neuroscience
• Cardiology

Background:

• Calmodulinopathies stem from calmodulin (CaM) mutations, causing cardiac arrhythmias like LQTS and CPVT.
• Neurological issues, including developmental delay and autism, are common in patients.
• CaM mutations impair CaV1.2 channel inactivation, explaining LQTS, but effects on other channels are unclear.

Purpose of the Study:

• Investigate how pathogenic CaM variants affect CaV1.3 and CaV2.1 channels, crucial for neuronal function.
• Explore the impact of CaM mutations on Ca2+/CaM-dependent inactivation (CDI) and Ca2+-dependent facilitation (CDF).
• Analyze CaM interactions with CaV1.3 and CaV2.1 IQ domains and Ca2+ sensing.

Main Methods:

• Examined CaM variant effects on CaV1.3 CDI and CaV2.1 CDF.
• Assessed CaM binding to CaV1.3 and CaV2.1 IQ domains.
• Investigated Ca2+ sensing by C-lobe CaM variants in complex with CaV IQ domains.

Main Results:

• Pathogenic CaM mutations impaired CaV1.3 CDI and disrupted CaV2.1 CDF.
• Most CaM variants bound to the IQ regions of both channels, with distinct interactions observed.
• C-lobe CaM variants showed reduced Ca2+ sensitivity when bound to CaV IQ domains.

Conclusions:

• Disrupted Ca2+/CaM regulation of CaV1.3 and CaV2.1 channels may contribute to calmodulinopathy pathogenesis.
• Unique CaM interactions with different voltage-gated calcium channel subtypes were identified.
• Impaired Ca2+ sensing by CaM variants underlies the observed regulatory deficits.