Machaca Lab

Research Interests

Welcome to Machaca Lab!

We are fascinated by the regulation of intracellular signaling pathways under both physiological and pathological conditions in the context of the regulation of oocyte maturation, meiotic arrest, cell cycle progression and secretion. We are particularly interested in Ca²⁺ signaling as a ubiquitous signaling module throughout phylogeny that is critical in mediating cellular responses to various cues. In fact, Ca²⁺signaling is often remodeled during cellular development and cellular pathology.

Oocyte maturation in preparation for fertilization offers a classical example of remodeling of calcium signaling during development. Fully grown oocytes in the ovary are not fertilizable until they undergo oocyte maturation, which encompasses both entry into meiosis, and a cytoplasmic differentiation that includes a dramatic remodeling of the Ca²⁺ signaling machinery. Ca²⁺ is the universal signal for egg activation at fertilization and for mediating the egg–to–embryo transition. Ca²⁺ signaling differentiation during oocyte maturation allows the egg to produce the specialized Ca²⁺ transient at fertilization to initiate egg activation. Ca²⁺ signaling remodeling affects both Ca²⁺ release and influx pathways including the IP₃ receptor, the store-operated Ca²⁺ entry, the plasma membrane Ca²⁺ ATPase, and the Ca²⁺–activated Cl- channels (CaCC). We are interested in the complex interplay between these Ca²⁺ signaling modules and effectors in the context of meiosis progression. We are also investigating the regulation of Ca²⁺ signaling pathways at the cellular level in various pathological conditions and cell types, including vascular smooth muscle cells in hypertension; breast cancer metastasis; and the role of Ca²⁺ signaling in regulating metabolism.

Ca²⁺ signals often lead to different cellular responses in the same cell. This specificity is encoded in part in the spatial and temporal features of Ca²⁺ signals to activate subsets of downstream effectors leading to a defined cellular response. We are investigating the mechanisms controlling this specificity by focusing on the SOCE pathway and IP₃-dependent Ca²⁺ release. We have recently described a novel Ca²⁺ signaling module that allows Ca²⁺ signaling in the mid-range spatially, between the classically defined Ca²⁺ micro-domain and global Ca²⁺ signals that cover the entire cell. Mid-range Ca²⁺ signaling occurs downstream of SOCE and uses ER tunnels to transport Ca²⁺ to specific effectors without inducing a global cytosolic Ca²⁺ rise (Ca²⁺ teleporting/tunneling). We have shown that CaCC are specifically activated by this pathway and are currently investigating other effectors.

Another emphasis in the Lab, consistent with the focus on signaling, is on the mechanisms controlling oocyte meiotic arrest in Xenopus. Vertebrate oocytes are arrested in prophase I for extended periods of time to allow for oocyte growth before maturation in preparation for fertilization. In Xenopus, meiotic arrest is released in response to steroids, particularly progesterone. We are interested in the mechanisms controlling meiotic arrest including the role of the progesterone receptor and the cAMP pathway and their interaction with the cell cycle kinase cascades.