Calcium Channels Are Ganging Up in the Sarcolemma

In this issue of Circulation Research , Navedo et al1 provide provocative and exciting data, indicating that up to ≈6 L-type Ca2+ channels (LTCCs) (in this case Cav1.2) can physically interact with each other to gate in a coupled manner, producing large and long-lasting Ca2+ influx into smooth and cardiac muscle myocytes. This coupling appears to be relatively rare and transient, with a minority of overall LTCCs involved at any moment. However, coupling is favored by either displacement of calmodulin (CaM) from its binding location in the C-terminal LTCC domain, activation of protein kinase (PK)Cα, chronic hypertension (in vascular smooth muscle), and LTCC mutants that are associated with cardiac arrhythmias and hearing loss in humans (ie, Timothy syndrome, or long QT syndrome 8).The fundamental observations here were made using total internal reflection fluorescence microscopy by measuring local submembrane Ca2+ events termed Ca2+ sparklets.2–4 These are attributable to Ca2+ entry via LTCC, unlike the sarcoplasmic reticulum (SR)/endoplasmic reticulum Ca2+ release events known as Ca2+ sparks or puffs (mediated by ryanodine or inositol 1,4,5 trisphosphate [InsP3] receptor channels). Physiologically Ca2+ sparklets would be extremely small and brief events, because normal LTCC openings are <1 ms in duration, and current amplitude is only ≈0.2 pA (at physiological [Ca2+]o) resulting in an integrated Ca2+ influx of only 0.1 femtocoulomb (or 300 Ca2+ ions).5 This would produce a very small hard to detect fluorescence signal. However, the Ca2+ sparklets here are much larger, which enhances detectability. They are larger because they are attributable to more rare persistent openings (like mode 2 openings favored by the LTCC agonist Bay K 8644),6 elevation of [Ca2+]o, and measurements at negative voltages …