Nesprin-1α contributes to the targeting of mAKAP to the cardiac myocyte nuclear envelope

Muscle A-kinase anchoring protein (mAKAP) is a scaffold protein found principally at the nuclear envelope of striated myocytes. mAKAP maintains a complex consisting of multiple signal transduction molecules including the cAMP-dependent protein kinase A, the ryanodine receptor calcium release channel, phosphodiesterase type 4D3, and protein phosphatase 2A. By an unknown mechanism, a domain containing spectrin repeats is responsible for targeting mAKAP to the nuclear envelope. We now demonstrate that the integral membrane protein nesprin-1α serves as a receptor for mAKAP on the nuclear envelope in cardiac myocytes. Nesprin-1α is inserted into the nuclear envelope by a conserved, C-terminal, klarsicht-related transmembrane domain and forms homodimers by the binding of an amino-terminal spectrin repeat domain. Through the direct binding of the nesprin-1α amino-terminal dimerization domain to the third mAKAP spectrin repeat, nesprin-1α targets mAKAP to the nuclear envelope. In turn, overexpression of these spectrin repeat domains in myocytes can displace mAKAP from nesprin-1α.