Voltage-gated Calcium Channel Ca_V1.2 functions in non-excitable musculoskeletal tissues

Most studies on Ca_V1.2 focus on its function in excitable cells such as cardiomyocytes and neurons, where frequent and dynamic changes in membrane potential facilitate activation of this voltage-gated channel. Few studies focused on Ca_V1.2 in non-excitable cells, which have more restricted changes in membrane potential. Studies of Timothy syndrome (TS), a multiorgan disorder caused by a de novo mutation (G406R) in the Ca_V1.2 pore forming α1C-encoding CACNA1C gene, however, revealed critical but previously unappreciated roles for Ca_V1.2 in many non-excitable cells.

The primary interest of the Cao Laboratory is to understand the physiological and pathophysiological contribution of Ca_V1.2 Ca²⁺ channel, its activation mechanisms and the molecular basis of Ca²⁺-dependent cellular processes during non-excitable musculoskeletal tissue (such as bone and tendon) development, postnatal growth and their repair/regeneration upon injury. Our long-term goal aims to translate our findings related to Ca²⁺ channel and Ca²⁺ signaling in basic bone and tendon biology to clinical trials in patients to help prevent and treat musculoskeletal diseases such as osteoporosis, tendinopathies, and heterotopic ossification in soft tissues. We utilize genetic mouse models, primary cell culture systems, pharmacological approaches, next-generation sequencing techniques, multiphoton Ca²⁺ imaging to define the molecular mechanisms and signaling cascades up/downstream of Ca_V1.2 in bone and tendon formation.