Pharmacological Sciences

Regulation of acetylcholine receptor genes in muscle

M.D., University Munich, 1966
Ph.D., University of California, Riverside, 1970
Schmidt Home Page at Department
of Biochemistry and Cell Biology

Research in the laboratory focuses on the regulation of acetylcholine
receptor (AChR) expression in skeletal muscle. We are especially interested
in two processes: 1) how receptor genes are turned on during differentiation,
i.e., when myoblasts fuse to form myofibers; and 2) how receptor genes are turned
off selectively in response to the electrical activity of the plasma membrane,
i.e., when the myofibers become innervated.

We have analyzed promoters of the alpha, gamma and delta subunit
genes and identified a consensus sequence which comprises as its core a CANNTG
motif or MyoD binding site. Our search for transcription factors that activate
this cis element is guided by the assumption that helix-loop-helix (HLH) proteins,
in particular the family of myogenic factors which recognize this motif, also
participate in the regulation of AChR genes; additional candidate proteins have
been identified by expression cloning. Using probes specific for these transcription
factors we have studied their expression during development and in the denervated
and denervated-stimulated muscle.

These experiments have revealed that the signaling pathway
linking membrane depolarization with AChR gene transcription involves the L-type
calcium channel in the plasma membrane and protein kinase C in the nucleus;
they also suggest that myogenin, which is rapidly phosphorylated and inactivated
by depolarization, functions in AChR gene control.

Selected Publications

• Huang, C.-F., Tong, J. and Schmidt,
  J. (1992) Protein kinase C couples membrane excitation to acetylcholine receptor
  gene inactivation in chick skeletal muscle. Neuron 9: 671-678.
• Huang, C.-F., Lee, Y.-S., Schmidt,
  M.M. and Schmidt, J. (1994) Rapid inhibition of myogenin-driven acetylcholine
  receptor subunit gene transcription. EMBO J. 13: 634-640.