What can naturally occurring mutations tell us about Cav1.x channel function?

Abstract

Voltage-gated Ca2 + channels allow for Ca2 +-dependent intracellular signaling by directly mediating Ca2 + ion influx, by physical coupling to intracellular Ca2 + release channels or functional coupling to other ion channels such as Ca2 + activated potassium channels. L-type Ca2 + channels that comprise the family of Cav1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in L-type Ca2 + channels and analyze their role in human diseases (Ca2 + channelopathies); e.g. mutations in Cav1.2 α1 cause Timothy and Brugada syndrome, mutations in Cav1.3 α1 are linked to sinoatrial node dysfunction and deafness while mutations in Cav1.4 α1 are associated with X-linked retinal disorders such as an incomplete form of congenital stationary night blindness. Herein, we also put the mutations underlying the channel's dysfunction into the structural context of the pore-forming α1 subunit. This analysis highlights the importance of combining functional data with structural analysis to gain a deeper understanding for the disease pathophysiology as well as for physiological channel function. This article is part of a Special Issue entitled: Calcium channels.

Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas

“…P1351R, V1353M and M1369I correspond to P1336R, V1338M and M1354I (NP_001122312, NP_001122311). Orange, malignant hyperthermia susceptibility; Light blue, hypokalemic periodic paralysis type 1; Green, timothy syndrome; Red, primary aldosteronism; Dark blue, congenital stationary blindness; Black dots, familial hemiplegic migraine; A circle with an arrow indicates a gain of function mutation shown by in vitro studies (Pietrobon 2002, Striessnig et al 2010, Azizan et al 2013, Scholl et al 2013, Stockner & Koschak 2013, Fernandes-Rosa et al 2014, Wang et al 2015. regulatory pathway are important for the tumorigenesis.…”

Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms

“…wild-type CACNA1F constructs and examined functionally in mammalian and oocyte expression systems by different groups. These in vitro studies showed that the different types of mutations can lead to changes in channel function by different transcript/ protein amount, by altered voltage dependence or both Hemara-Wahanui et al, 2005;Hoda et al, 2005Hoda et al, , 2006McRory et al, 2004;Stockner and Koschak, 2013). Reduced channel stability that might promote misfolding of Cav.1 channels has been recently indicated as a possible pathogenic mechanism (Burtscher et al, 2014).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Structural aberrations identified in CSNB2 patients comprise Ca V 1.4 a1-subunit missense or truncation mutations in addition to insertions or deletions, which can be categorized by their functional effects as loss or gain of function or impairment of the CTM (see above) (Stockner and Koschak, 2013). The complete absence of channel function or altered gating properties is expected to eliminate or decrease Ca V 1.4-mediated Ca 2+ entry required for normal photoreceptor signaling.…”