CD38/ADP-ribose/TRPM2-mediated nuclear Ca²⁺ signaling is essential for hepatic gluconeogenesis in fasting and diabetes.

ABSTRACT: Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD⁺ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca²⁺ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribo

SUBMITTER: Rah SY 

PROVIDER: S-EPMC10393965 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature