Ion channels are integral membrane proteins that help establish and control the small voltage gradient across the plasma membrane of living cells by allowing the flow of ions down their electrochemical gradient. Where some ion channels permit the passage of ions based on charge, others conduct based on an ionic species, such as sodium or potassium. Furthermore, in some ion channels, the passage is governed by a gate which is controlled by chemical or electrical signals, temperature or mechanical forces. There are a few main classifications of gated ion channels. The first are voltage-gated ion channels which open and close in response to membrane potential. These are then separated into sodium, calcium, potassium, proton, transient receptor and cyclic nucleotide-gated channels. Ligand-gated ion channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. The other gated classifications include activation and inactivation by second messengers, inward-rectifier potassium channels, calcium-activated potassium channels, two-pore-domain potassium channels, light-gated channels, mechano-sensitive ion channels and cyclic nucleotide-gated channels. Finally, the other classifications are based on less normal characteristics such as two-pore channels, and transient receptor potential channels. Specifially, Cav1.2 is a cardiac L-type calcium channel, and is important for excitation and contraction of the heart. It may be associated with a variant of Long QT syndrome called Timothy's syndrome and also with Brugada syndrome. Some references also suggest it is related to bipolar disease as well.