How Your Muscles Know You've Been Working Out: The [IP.sub.3] Pathway as a Developmental Signal in Skeletal Muscle

We study the function of inositol trisphosphate ([IP.sub.3]) receptors in skeletal muscle. The [IP.sub.3] signaling pathway, which triggers intracellular calcium release, is widespread in cells, participating in processes from fertilization to platelet aggregation. Surprisingly, it has not been well explored in skeletal muscle cells; we think this is because muscle has another, headline grabbing, [Ca.sup.2+] signaling system, excitation-contraction coupling. We believe that in skeletal muscle the [IP.sub.3] pathway mediates a second [Ca.sup.2+]-dependent pathway that participates in producing long term--i.e., gene-expression-dependent--changes in muscle cells. Using immunocytochemistry to determine the distribution of [IP.sub.3] receptors, relative to proteins of known intracellular location, we find that the receptors are positioned appropriately to mediate a slowly propagating wave of calcium release that follows the rapid rise in calcium triggered by depolarization. This second wave, which lights up the nuclei as it moves across fluo-3 -ontaining cultured cells, can be inhibited by the [IP.sub.3] blocker 2-APB; the fast rise in [Ca.sup.2+], associated with contraction, is unaffected by this treatment. 2-APB also blocks the depolarization induced activation of ERKs 1 and 2 and CREB, proteins that mediate changes in gene expression. We think that this [IP.sub.3]-dependent [Ca.sup.2+] signaling system may be one mechanism by which muscle cells control hypertrophy and atrophy through effects on both myonuc!ei and satellite cells.