Calcium homeostasis has major roles in different extra and intra cellular processes and is therefore crucial for cell physiology. CALHM channel gating is regulated allosterically by both voltage and Ca2+ concentration. Low concentrations of Ca2+ and depolarization cause channel activation. The molecular basis for voltage-dependent gating remains unknown. CALHM3 channels do not have canonical voltage sensors as found in other channels. CALHM channels poorly discriminate cations and anions enabling signaling molecules such as Ca2+ and ATP to permeate to its pore. This suggests a non-discriminatory ion selectivity filter or a wide ion conduction pore. Recent studies have shown that it is the latter and not the former that accounts for weak ion selectivity.