Type II cGMP-dependent protein kinase (cGK II) is the protein product of one of two genes coding for cGKs in mammalian genomes. cGK II has a domain structure similar to cGK I (alpha or beta) consisting of an N-terminal regulatory domain, which contains a dimerization and an autoinhibitory region, two cGMP-binding domains and a C-terminal catalytic domain. However, the position of the high and low affinity cGMP-binding-domains in cGK II are reversed in comparison to cGK I. Moreover, the isoenzymes exhibit a different affinity towards various membrane permeable cGMP-analogs, allowing differentiation between the cGKs. Type II cGK is bound to the membrane by a myristoyl moiety. It has a distinct function and an expression pattern distinct from that of cGKI, being expressed predominantly in intestine, brain, and kidney. It is involved in regulating electrolyte and water secretion by epithelial tissues in response to the luminocrinic hormones guanylin and uroguanylin and in the secretory diarrhea provoked by heat-stable enterotoxins. Type II cGK also plays a role in the regulation of endochondral ossification by C-type natriuretic peptide, in renin secretion by the kidney, aldosterone secretion by the adrenal, and in the adjustment of the biological clock.