Abstract
ABSTRACTThe copy number of membrane proteins at the cell surface is tightly regulated. Many ion channels and receptors present retrieval motifs to COPI vesicle coats and are retained in the early secretory pathway. In some cases, the interaction with COPI is prevented by binding to 14-3-3 proteins. However, the functional significance of this antagonism between COPI and 14-3-3 in terminally differentiated cells is unknown. Here, we show that ATP-sensitive K+ (KATP) channels, which are composed of Kir6.2 and SUR1 subunits, are stalled in the Golgi complex of ventricular, but not atrial, cardiomyocytes. Upon sustained β-adrenergic stimulation, which leads to activation of protein kinase A (PKA), SUR1-containing channels reach the plasma membrane of ventricular cells. We show that PKA-dependent phosphorylation of the C-terminus of Kir6.2 decreases binding to COPI and, thereby, silences the arginine-based retrieval signal. Thus, activation of the sympathetic nervous system releases this population of KATP channels from storage in the Golgi and, hence, might facilitate the adaptive response to metabolic challenges.
Highlights
Hormone signaling rapidly adapts the function of cells to the physiological requirements of the organism
Confocal image sections confirmed previous observations that had been obtained by scanning ion conductance microscopy (Korchev et al, 2000) that, in ventricular myocytes, SUR2A and Kir6.2 colocalized at the cell surface and at striations where transverse (T-)tubule membrane invaginations occur (Fig. 1B)
Both sulfonylurea receptor type-1 (SUR1) and SUR2A are glycoproteins; SUR1 is Nglycosylated at positions Asn10 and Asn1050 (Conti et al, 2002), and sites for N-glycosylation are predicted at Asn9 and Asn330 of SUR2
Summary
Hormone signaling rapidly adapts the function of cells to the physiological requirements of the organism. Regulated translocation of ion channels and transporters to the plasma membrane is one important mechanism of the cellular response. Prominent examples include insulin-triggered GLUT4 translocation (Bogan, 2012) and growth-hormone-induced translocation of TRPC5 channels (Abe and Puertollano, 2011; Bezzerides et al, 2004). We consider the metabolically-sensitive ATP-sensitive K+ (KATP) channel as an example of a heteromultimeric cargo protein that is stored in, and released from, the Golgi compartment upon hormoneinduced signal transduction
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