Ca²⁺ Signaling and Ion Channel Function in Smooth Muscle

Smooth muscle, lining along the walls of virtually all hollow organs, plays pivotal roles in physiological functions such as maintaining blood pressure and regulating bronchial tone.  Defects in this type of cell cause congenital and acquired pathological conditions such as hypertension and asthma.  Intracellular calcium is a primary signal in mediating smooth muscle function and ion channels are the major molecules to set the calcium level in smooth muscle.  Research in our laboratory is focused on the quantitative understanding of the ways Ca²⁺ signals and ion channel activities are controlled and regulated in smooth muscle.

We have been studying highly localized, short-lived Ca²⁺ transients so called “Ca²⁺ sparks” that result from the opening of a few clustered ryanodine receptors (RyRs) in the membrane of sarcoplasmic reticulum (SR).  These local Ca²⁺ signals are the elementary events of global changes of Ca²⁺ in striated muscles and neurons.  In smooth muscle from airways, corpora cavernosa, and some blood vessels, Ca²⁺ sparks act in their own right to trigger a cluster of big-conductance Ca²⁺-activated K⁺ (BK) channels and Ca²⁺-activated Cl^- (Cl_(Ca)) channels in the vicinity of release sites (see Fig. 1).  Activation of these two types of channels produces spontaneous transient outward currents (STOCs) and spontaneous transient inward currents (STICs), respectively, which in turn regulate the activities of Ca²⁺-permeable channels.  We recently found that Ca²⁺ sparks function as stabilizers of membrane potential and control the contractile state of airway smooth muscle.  We are aiming to elucidate mechanisms on how Ca²⁺ sparks activate the BK and Cl_(Ca) channels, to investigate the structure and function of Cl_(Ca) channels, and to determine the roles of Ca²⁺ spark signaling in asthma and other smooth muscle disorders.  Our methods include patch-clamp, 2D and 3D visualization of channel protein cellular distribution, in vitro bioassays, molecular biology, transgenic mouse models, computer modeling, and high-speed wide-field microscopy developed by the Biomedical Imaging Group (http://invitro.umassmed.edu/).