Cardiac L-type calcium channel regulation by Leucine-Rich Repeat-Containing Protein 10

ABSTRACT

L-type calcium channels (LTCCs), the major portal for Ca²⁺ entry into cardiomyocytes, are essential for excitation-contraction coupling and thus play a central role in regulating overall cardiac function. LTCC function is finely tuned by multiple signaling pathways and accessory proteins. Leucine-rich repeat-containing protein 10 (LRRC10) is a little studied cardiomyocyte-specific protein recently identified as a modulator of LTCCs. LRRC10 exerts a remarkable effect on LTCC function, more than doubling L-type Ca²⁺ current (I_Ca,L) amplitude in a heterologous expression system by altering the gating of the channels without changing their surface membrane expression. Genetic ablation of LRRC10 expression in mouse and zebrafish hearts leads to a significant reduction in I_Ca,L density and a slowly progressive dilated cardiomyopathy in mice. Rare sequence variants of LRRC10 have been identified in dilated cardiomyopathy and sudden unexplained nocturnal cardiac death syndrome, but these variants have not been clearly linked to disease. Nevertheless, the DCM-associated variant, I195T, converted LRRC10 from a I_Ca,L potentiator to a I_Ca,L suppressor, thus illustrating the wide dynamic range of LRRC10-mediated I_Ca,L regulation. This review focuses on the contemporary knowledge of LTCC modulation by LRRC10 and discusses potential directions for future investigations.

KEYWORDS:

• L-type calcium channels
• LRRC10
• electrophysiology
• cardiomyocyte
• heart

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

NS and TJK conceptualized the review, reviewed and interpreted the literature, drafted and revised the manuscript, and approved the version of manuscript to be published. All authors agree to be accountable for all aspects of the work.

Data availability statement

Data availability is not applicable as no new data were generated for this review article.

Additional information

Funding

This work is supported by American Heart Association Predoctoral Fellowship 23PRE1027057 (NS), NIH U01 HL134764 (TJK), NSF 1648035 (TJK), and UW-Madison Stem Cell and Regenerative Medicine Professorship (TJK).