"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins (as opposed to the subclass of smaller, monomeric small GTPases) . These proteins are activated by G protein-coupled receptors and are made up of alpha (α), beta (β) and gamma (γ) subunits, the latter two referred to as the beta-gamma complex.

There are four main families of G proteins: Gi/Go, Gq, Gs, and G12.

Alpha subunits

Reconstitution experiments carried out in the early 1980s showed that purified G_α subunits can directly activate effector enzymes. The GTP form of the α subunit of transducin (G_t) activates the cyclic GMP phosphodiesterase from retinal rod outer segments, and the GTP form of the α subunit of the stimulatory G protein (G_s) activates hormone-sensitive adenylate cyclase.

G_α subunits consist of two domains, the GTPase domain, and the alpha-helical domain.

There exist at least 20 different G_α subunits, which are separated into four main families. This nomenclature is based on their sequence homologies: