Ca²⁺/Calmodulin-Dependent Protein Kinase II Signaling in Vascular Smooth Muscle

Abstract

Ca²⁺ signaling pathways regulate diverse basic and differentiated cell functions including gene transcription, proliferation, and contraction of vascular smooth muscle. A key mediator of Ca²⁺ signals is the multifunctional serine/threonine protein kinase Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). CaMKII is structurally complex and has unusual autoregulatory properties. Because of this, there is a general lack of expertise and specific tools for studying its specific functions and relevant protein substrates have been difficult to identify. Biochemical and molecular studies have resulted in identification of multiple isoforms of the kinase expressed in differentiated vascular smooth muscle, where it has been implicated in the regulation of contractile function. Potential targets are diverse and the function of different isoforms is not well defined. In cultured vascular smooth muscle, different isoforms are expressed and associated with regulation of proliferation and migration. With recent accumulation of knowledge regarding the specific isoforms of CaMKII expressed in arterial smooth muscle and consequent development of isoform-specific molecular approaches for modifying expression and activity, progress on identifying CaMKII-dependent functions is foreseeable. Studies using these approaches indicate that dynamic regulation of CaMKII isozyme composition is an important determinant of, and contributor to, vascular smooth muscle phenotype modulation that is a component of fibroproliferative vascular disease.