Figure 1. Main Ca2+ influx pathways regulating Ca2+-sparks in young and aged mesenteric vascular smooth muscle cells (VSMCs). Opening of clustered RyRs in the SR produces Ca2+-sparks that activate BKCa channels providing a negative feedback effect on vasoconstriction. CaV1.2 L-type channels contribute to global cytosolic [Ca2+], thereby influencing luminal SR calcium (via SERCA) and generating the majority (75%) of Ca2+-sparks. Caveolae position CaV3.2 T-type channels close to RyRs for extracellular Ca2+-influx to trigger (~25%) Ca2+-sparks. In aged mice VSMCs, this CaV3.2-RyR pathway is lost. Instead, a gadolinium-sensitive Ca2+-influx pathway triggering (20%) Ca2+-sparks is upregulated. Nonselective TRP channels might be involved in this pathway. BKCa, Ca2+-activated K+ channels; RyR2, ryanodine receptor subtype 2; SERCA, sarcoplasmic/endoplasmic calcium pump; SR, sarcoplasmic reticulum.