In a shock move, Number 10 head of strategic comms Tim Chatwin handed in his resignation last week.
Chatwin works closely with strategy director Steve Hilton and also plays a crucial role overseeing the Number 10 news grid. He is understood to be moving to the US to take up a top strategic comms role with Google, where Hilton's wife Rachael Whetstone is VP of global comms.
A Google spokesman confirmed that Chatwin was joining but declined to provide further details.
It is understood that no decision has been made on how Chatwin will be replaced in Downing Street.
In addition, Number 10 head of policy James O'Shaughnessy is also said to be poised to quit. His departure has not yet been confirmed by Number 10, but O'Shaughnessy has told friends that he is ready to move on.
His comments follow a reshuffle of Cameron's top team earlier this year that saw former KPMG partner Paul Kirby brought in as head of policy development. Kirby now leads a team of eight civil servants in formulating government policy.
Both departures were exclusively revealed on prweek.com (2 September).
A Downing Street insider said: 'James' nose has been put out of joint for a while with all of these civil servants coming in doing policy. He knows he's been slightly pushed to the margins.
'But Tim is an absolute bolt out of the blue. He's an uber-loyalist - I always thought he would be last man standing.'
It is believed that Chatwin's departure could leave Cameron's Number 10 team lacking in long-term strategic comms thinking. One senior Whitehall source who has worked with Chatwin said: 'Tim is an unsung hero. While everybody else is very tactical, he is the one with the strategic comms brain.'